EP0596326B1 - Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes, their salts, medicaments containing the same, use thereof and precesses for their production - Google Patents

Abstract

The invention relates to arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula <IMAGE> in which n, m, p, A, W<1>, W<2>, X, Y and R<1> to R<11> are defined as in Claim 1, their isomers and isomer mixtures and their salts, which have useful properties and in particular exert an inhibitory action on cholesterol biosynthesis.

Description

The present invention relates to arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes, their salts with physiologically compatible organic and inorganic acids, processes for the preparation of these compounds and medicaments containing them.

The compounds according to the invention are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase, a key enzyme of cholesterol biosynthesis. The compounds according to the invention are suitable for the treatment and prophylaxis of hyperlipidemia, hypercholesterolemia and atherosclerosis. Further possible areas of application arise for the treatment of hyperproliferative skin and vascular diseases, tumors, gallstone disorders and mycoses.

Compounds that interfere with cholesterol biosynthesis are important for the treatment of a number of clinical pictures. Hypercholesterolemias and hyperlipidemias, which are risk factors for the development of atherosclerotic vascular changes and their complications such as coronary heart disease, cerebral ischemia, intermittent claudication and gangrene, are particularly worth mentioning here.

The importance of excessive serum cholesterol levels as the main risk factor for the development of atherosclerotic vascular changes is widely recognized. Extensive clinical studies have led to the finding that lowering the serum cholesterol can reduce the risk of developing coronary heart diseases (Current Opinion in Lipidology 2 (4), 234 [1991]). Since most of the cholesterol is synthesized in the organism itself and only a small part is ingested with food, the inhibition of biosynthesis is a particularly attractive way to lower the elevated cholesterol level.

In addition, the treatment of hyperproliferative skin and vascular diseases as well as tumor diseases, the treatment and prophylaxis of gallstone disorders and the use in mycoses are described as further possible areas of application of cholesterol biosynthesis inhibitors. In the latter case, this involves an intervention in ergosterol biosynthesis in fungal organisms, which is largely analogous to cholesterol biosynthesis in mammalian cells.

Cholesterol or ergosterol biosynthesis proceeds from acetic acid over a large number of reaction steps. This multi-stage process offers a number of intervention options, examples of which are:
For the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, β-lactones and β-lactams with potential antihypercholesterolemic activity are mentioned (see J. Antibiotics 40 , 1356 [1987], US-A -4,751,237, EP-A-0 462 667, US-A-4,983,597).

Inhibitors of the enzyme HMG-CoA reductase are 3,5-dihydroxycarboxylic acids of the mevinoline type and their δ-lactones, the representatives of which lovastatin, simvastatin and pravastatin are used in the therapy of hypercholesterolemia. Further possible fields of application of these compounds are fungal infections (US-A-4,375,475, EP-A-0 113 881, US-A-5,106,992), skin diseases (EP-A-0 369 263) and Gallstone disease and tumor diseases (US-A-5,106,992; Lancet 339 , 1154-1156 [1992]). Inhibition of smooth muscle cell proliferation by lovastatin is described in Cardiovasc. Drugs. Ther. 5 , Suppl. 3, 354 [1991].

Inhibitors of the enzyme squalene synthetase are, for example, isoprenoid (phosphinylmethyl) phosphonates, the suitability of which for the treatment of hypercholesterolemia, gallstone disorders and tumor diseases is described in EP-A-0 409 181 and J. Med. Chemistry 34 , 1912 [1991], furthermore the Squalestatine with cholesterol-lowering and antifungal effects (J. Antibotics 45 , 639-647 [1992] and J. Biol. Chemistry 267 , 11705-11708 [1992].

Known inhibitors of the enzyme squalene epoxidase are allylamines such as naftifin and terbinafine, which have found use in the treatment of fungal diseases, and allylamine NB-598 with antihypercholesterolemic activity (J. Biol. Chemistry 265 , 18075-18078, [1990 ]) and fluorosquale derivatives with hypocholesterolemic activity (US-A-5,011,859). Furthermore, piperidines and azadecalines with potential hypocholesterolemic and / or antifungal effects are described, the mechanism of which has not been clearly established and which squalene epoxidase and / or 2,3-epoxysqualene lanosterol cyclase inhibitors are (EP-A-0 420 116, EP-A-0 468 434, US-A-5,084,461 and EP-A-0 468 457).

Examples of inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase are diphenyl derivatives (EP-A-0 464 465), aminoalkoxybenzene derivatives (EP-A-0 410 359) and piperidine derivatives (J. Org. Chem. 57 , 2794-2803, [1992]), which have an antifungal effect. Furthermore, this enzyme is produced in mammalian cells by decalin, azadecalin and indane derivatives (WO 89/08450, J. Biol. Chemistry 254 , 11258-11263 [1981], Biochem. Pharmacology 37 , 1955-1964 [1988] and J 64 003 144) , further by 2-aza-2,3-dihydrosqualene and 2,3-epiminosqualen (Biochem. Pharmacology 34 , 2765-2777 [1985]), by squalenoid-epoxy vinyl ether (J. Chem. Soc. Perkin Trans. I, 1988 , 461) and 29-methylidene-2,3- oxidosqualen (J. Amer. Chem. Soc. 113 , 9673-9674 [1991]) inhibited.

Finally, inhibitors of the enzyme lanosterol-14α-demethylase also include steroid derivatives with potential antihyperlipemic activity which simultaneously influence the enzyme HMG-CoA reductase (US Pat. No. 5,041,432, J. Biol. Chemistry 266 , 20070-20078 [1991] , US-A-5,034,548). In addition, this enzyme is inhibited by the azole-type antifungals, which are N-substituted imidazoles and triazoles. This class includes, for example, the antifungals ketoconazole and fluconazole on the market.

The compounds of the general formula I below are new. It has surprisingly been found that they are very effective inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase (international classification: EC5.4.99.7).

The enzyme 2,3-epoxysqualen-lanosterol cyclase catalyzes a key step in cholesterol or ergosterol biosynthesis, namely the conversion of 2,3-epoxis torment into lanosterol, the first compound with a steroid structure in the biosynthesis cascade. Inhibitors of this enzyme have the advantage of higher selectivity compared to inhibitors of earlier biosynthesis steps, such as HMG-CoA synthase and HMG-CoA reductase, because the inhibition of these early biosynthesis steps leads to a decrease in biosynthetically formed mevalonic acid and thereby also the biosynthesis of the mevalonic acid-dependent substances Can affect dolichol, ubiquinone and isopentenyl-t-RNA negatively (cf. J. Biol. Chemistry 265 , 18075-18078 [1990]).

If biosynthesis steps are inhibited after the conversion of 2,3-epoxysqualene into lanosterol, there is a risk of Accumulation of intermediate products with a steroid structure in the organism and the triggering of toxic effects caused thereby. This is described for example for triparanol, a desmosterol reductase inhibitor. This substance had to be withdrawn from the market because of the formation of cataracts, ichthyosis and alopecia (cited in J. Biol. Chemistry 265 , 18075-18078 [1990]).

As already explained at the beginning, inhibitors of 2,3-epoxysqualene-lanosterol cyclase have been described individually in the literature. However, the structures of these compounds are completely different from the structure of the compounds of the general formula I mentioned below.

The invention relates to the provision of antihypercholesterolemic substances which are suitable for the treatment and prophylaxis of atherosclerosis and, in comparison to known active substances, are distinguished by a better antihypercholesterolemic effect with increased selectivity and thus increased safety. Since the compounds according to the invention can also inhibit ergosterol biosynthesis in the fungal organism due to their high activity as inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase, they are also suitable for the treatment of mycoses.

In der allgemeinen Formel I bedeuten
n die Zahlen 0 oder 1,
m die Zahlen 1 oder 2,
p die Zahlen 0 oder 1,
A eine Einfachbindung, eine geradkettige oder verzweigte Alkylengruppe mit 1 bis 17 Kohlenstoffatomen, eine Alkenylengruppe mit 2 bis 17 Kohlenstoffatomen oder eine Alkinylengruppe mit 2 bis 4 Kohlenstoffatomen,
W¹ und W² jeweils ein Wasserstoffatom oder zusammen eine Kohlenstoff-Kohlenstoffbindung,
X eine Carbonyl- oder Sulfonylgruppe,
Y ein Sauerstoff- oder Schwefelatom oder eine 〉NR¹¹-Gruppe,
R¹ bis R⁶ jeweils ein Wasserstoffatom oder
einer, zwei oder drei der Reste R¹ bis R⁶, wobei die Reste gleich oder verschieden sein können, eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, die durch eine Hydroxy-, Alkoxy-, Alkylthio- oder Dialkylaminogruppe oder durch eine gegebenenfalls durch ein Halogenatom oder eine Alkylgruppe substituierte Phenylgruppe substituiert sein kann, oder eine Alkoxycarbonylgruppe und die übrigen der Reste R¹ bis R⁶ jeweils ein Wasserstoffatom,
wobei einer, zwei oder alle drei der Reste R¹, R³ und R⁵ auch eine gegebenenfalls durch eine Alkylgruppe oder ein Halogenatom substituierte Phenylgruppe bedeuten können,
R⁷ ein Wasserstoff- oder Halogenatom, eine Alkyl- oder Alkoxygruppe,
R⁸ und R⁹ unabhängig voneinander jeweils ein Wasserstoffatom oder eine Alkylgruppe,
R¹⁰ ein Wasserstoffatom, eine Cycloalkylgruppe mit 3 bis 6 Kohlenstoffatomen, eine gegebenenfalls durch ein Halogenatom, eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine Trifluormethyl-, Alkoxy-, Cyano-, Nitro-, Alkylsulfonyl- oder Phenylgruppe substituierte Phenylgruppe, eine durch zwei Trifluormethylgruppen, zwei bis fünf Halogenatome oder durch ein Halogenatom und eine Alkylgruppe substituierte Phenylgruppe, eine gegebenenfalls durch ein Fluoratom substituierte Naphthyl- oder Tetrahydronaphthylgruppe, eine Pyridylgruppe oder eine gegebenenfalls durch ein Halogenatom oder eine Alkylgruppe substituierte Thienylgruppe,
R¹¹ ein Wasserstoffatom oder eine Alkylgruppe,
wobei A keine Einfachbindung sein kann, wenn X die Sulfonylgruppe und R¹⁰ ein Wasserstoffatom bedeuten, und
wobei, sofern nichts anderes erwähnt wurde, die vorstehend erwähnten Alkyl-, Alkoxy-, Alkylthio- und Alkylsulfonylreste jeweils 1 bis 3 Kohlenstoffatome enthalten können und die vorstehend erwähnten Halogenatome jeweils ein Fluor-, Chlor- oder Bromatom bedeuten können.The arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the present invention and their salts have the general formula I. The compounds can optionally also be in the form of enantiomers, diastereomers or mixtures thereof.

In the general formula I mean
n the numbers 0 or 1,
m the numbers 1 or 2,
p the numbers 0 or 1,
A is a single bond, a straight-chain or branched alkylene group with 1 to 17 carbon atoms, an alkenylene group with 2 to 17 carbon atoms or an alkynylene group with 2 to 4 carbon atoms,
W¹ and W² each represent a hydrogen atom or together a carbon-carbon bond,
X is a carbonyl or sulfonyl group,
Y is an oxygen or sulfur atom or a〉 NR¹¹ group,
R¹ to R⁶ each represent a hydrogen atom or
one, two or three of the radicals R¹ to R⁶, where the radicals may be the same or different, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which may be replaced by a hydroxyl, alkoxy, alkylthio or dialkylamino group or by an optionally Halogen atom or an alkyl group substituted phenyl group, or an alkoxycarbonyl group and the rest of the radicals R¹ to R⁶ each have a hydrogen atom,
where one, two or all three of the radicals R¹, R³ and R⁵ can also mean a phenyl group which is optionally substituted by an alkyl group or a halogen atom,
R⁷ represents a hydrogen or halogen atom, an alkyl or alkoxy group,
R⁸ and R⁹ independently of one another each represent a hydrogen atom or an alkyl group,
R¹⁰ is a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by a halogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl, alkoxy, cyano, nitro, alkylsulfonyl or phenyl group, one by two trifluoromethyl groups, two to five halogen atoms or a phenyl group substituted by a halogen atom and an alkyl group, a naphthyl or tetrahydronaphthyl group optionally substituted by a fluorine atom, a pyridyl group or a thienyl group optionally substituted by a halogen atom or an alkyl group,
R¹¹ is a hydrogen atom or an alkyl group,
where A cannot be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
unless otherwise mentioned, the alkyl, alkoxy, alkylthio and alkylsulfonyl radicals mentioned above may each contain 1 to 3 carbon atoms and the halogen atoms mentioned above may each represent a fluorine, chlorine or bromine atom.

in der
n die Zahlen 0 oder 1,
m die Zahlen 1 oder 2,
p die Zahl 0 oder 1,
A eine Einfachbindung, eine geradkettige oder verzweigte Alkylengruppe mit 1 bis 17 Kohlenstoffatomen, eine Alkenylengruppe mit 2 bis 4 Kohlenstoffatomen oder eine Alkinylengruppe mit 2 bis 4 Kohlenstoffatomen,
W¹ und W² jeweils ein Wasserstoffatom oder zusammen eine Kohlenstoff-Kohlenstoffbindung,
X eine Carbonyl- oder Sulfonylgruppe,
Y ein Sauerstoff- oder Schwefelatom oder eine 〉NR¹¹-Gruppe,
R¹ bis R⁴ jeweils ein Wasserstoffatom oder
einer oder zwei der Reste R¹ bis R⁴ unabhängig voneinander jeweils eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, die durch eine Hydroxy-, Alkylthio- oder Dialkylaminogruppe oder durch eine gegebenenfalls durch ein Halogenatom substituierte Phenylgruppe substituiert sein kann, oder eine Phenylgruppe und die übrigen der Reste R¹ bis R⁴ jeweils ein Wasserstoffatom,
R⁵ und R⁶, die gleich oder verschieden sein können, ein Wasserstoffatom oder eine Methylgruppe,
R⁷ ein Wasserstoff- oder Halogenatom, eine Alkyl- oder Alkoxygruppe,
R⁸ ein Wasserstoffatom oder eine Alkylgruppe,
R⁹ ein Wasserstoffatom,
R¹⁰ ein Wasserstoffatom, eine Cycloalkylgruppe mit 3 bis 6 Kohlenstoffatomen, eine gegebenenfalls durch ein oder zwei Halogenatome, eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine Trifluormethyl-, Methoxy-, Cyano-, Nitro-, Methylsulfonyl- oder Phenylgruppe substituierte Phenylgruppe, eine durch zwei Trifluormethylgruppen oder durch ein Halogenatom und eine Methylgruppe substituierte Phenylgruppe, eine durch drei bis fünf Fluoratome substituierte Phenylgruppe, eine gegebenenfalls durch ein Fluoratom substituierte Naphthylgruppe, eine Tetrahydronaphthyl- oder Pyridylgruppe oder eine gegebenenfalls durch ein Halogenatom substituierte Thienylgruppe und
R¹¹ ein Wasserstoffatom oder eine Alkylgruppe bedeuten,
wobei A keine Einfachbindung sein kann, wenn X die Sulfonylgruppe und R¹⁰ ein Wasserstoffatom bedeuten, und
wobei, sofern nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylreste jeweils 1 bis 3 Kohlenstoffatome enthalten können und die vorstehend erwähnten Halogenatome jeweils ein Fluor-, Chlor- oder Bromatom bedeuten können, deren Enantiomere, Diastereomere und deren Salze.The compounds of the general formula Ia are preferred,

in the
n the numbers 0 or 1,
m the numbers 1 or 2,
p is the number 0 or 1,
A is a single bond, a straight-chain or branched alkylene group with 1 to 17 carbon atoms, an alkenylene group with 2 to 4 carbon atoms or an alkynylene group with 2 to 4 carbon atoms,
W¹ and W² each represent a hydrogen atom or together a carbon-carbon bond,
X is a carbonyl or sulfonyl group,
Y is an oxygen or sulfur atom or a〉 NR¹¹ group,
R¹ to R⁴ each represent a hydrogen atom or
one or two of the radicals R¹ to R⁴ independently of one another each have a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which can be substituted by a hydroxyl, alkylthio or dialkylamino group or by a phenyl group which is optionally substituted by a halogen atom, or a phenyl group and that the rest of the radicals R¹ to R⁴ each have a hydrogen atom,
R⁵ and R⁶, which may be the same or different, represent a hydrogen atom or a methyl group,
R⁷ represents a hydrogen or halogen atom, an alkyl or alkoxy group,
R⁸ represents a hydrogen atom or an alkyl group,
R⁹ is a hydrogen atom,
R¹⁰ is a hydrogen atom, a cycloalkyl group with 3 to 6 carbon atoms, a phenyl group optionally substituted by one or two halogen atoms, a straight-chain or branched alkyl group with 1 to 4 carbon atoms, a trifluoromethyl, methoxy, cyano, nitro, methylsulfonyl or phenyl group , a phenyl group substituted by two trifluoromethyl groups or by a halogen atom and a methyl group, a phenyl group substituted by three to five fluorine atoms, a naphthyl group optionally substituted by a fluorine atom, a tetrahydronaphthyl or pyridyl group or a thienyl group optionally substituted by a halogen atom and
R¹¹ represents a hydrogen atom or an alkyl group,
where A cannot be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
where, unless stated otherwise, the above-mentioned alkyl radicals can each contain 1 to 3 carbon atoms and the above-mentioned halogen atoms can each represent a fluorine, chlorine or bromine atom, their enantiomers, diastereomers and their salts.

The compounds of the general formula Ia in which
n the numbers 0 or 1,
m the numbers 1 or 2,
p the numbers O or 1,
A is a single bond, a straight-chain or branched alkylene group with 1 to 17 carbon atoms or an alkenylene group with 2 to 4 carbon atoms,
W¹ and W² each represent a hydrogen atom or together a carbon-carbon bond,
X is a carbonyl or sulfonyl group,
Y is an oxygen atom or a〉 NR¹¹ group,
R¹ to R⁴ each represent a hydrogen atom or
one or two of the radicals R¹ to R⁴ independently of one another each have a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and the rest of the radicals R¹ to R⁴ each have a hydrogen atom,
R⁵ and R⁶, which may be the same or different, represent a hydrogen atom or a methyl group,
R⁷ is a hydrogen or halogen atom, a methyl or methoxy group,
R⁸ is a hydrogen atom or a methyl group,
R⁹ is a hydrogen atom,
R¹⁰ is a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group which is optionally substituted by one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl groups or by a halogen atom and an alkyl group, one in the 4-position a 1-naphthyl group optionally substituted by a fluorine atom, a 2-naphthyl group, a 1,2,3,4-tetrahydro-2-naphthyl group, a pyridyl or 4-biphenyl group or a thienyl group optionally substituted by a halogen atom and
R¹¹ represents a hydrogen atom or a methyl group,
where A cannot be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
where, unless stated otherwise, the above-mentioned alkyl parts may each contain 1 to 3 carbon atoms and the above-mentioned halogen atoms may each represent a fluorine or chlorine atom, their enantiomers, diastereomers and their salts.

• (1) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
• (2) 1-(4-Chlorbenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzyliden]piperidin
• (3) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(4-trifluormethylbenzoyl)piperidin
• (4) 1-(4-Chlor-3-methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
• (5) 1-(4-Fluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
• (6) 1-(5-Chlor-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
• (7) 1-Cyclohexancarbonyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin,
• (8) 4-[4-(2-Oxazolin-2-yl)benzyl]-1-(4-trifluormethylbenzoyl)piperidin
• (9) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
• (10) 1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl)benzyliden]pyrrolidin
• (11) 1-(4-Chlorbenzoyl)-4-[2-fluor-4-(2-oxazolin-2-yl)benzyliden]piperidin
• (12) 1-(4-Chlorbenzoyl)-4-[3-methyl-4-(2-oxazolin-2-yl)benzyliden]piperidin

und deren Salze.The compounds of the general formula Ia in which
n the numbers 0 or 1,
m the number 1,
p the numbers O or 1,
A a single bond,
W¹ and W² each represent a hydrogen atom or together a carbon-carbon bond,
X is a carbonyl group,
Y is an oxygen atom,
R¹ to R⁶ each represent a hydrogen atom,
R⁷ represents a hydrogen or halogen atom or a methyl group,
R⁸ and R⁹ each represent a hydrogen atom,
R¹⁰ is a phenyl group substituted by a fluorine, chlorine or bromine atom or a trifluoromethyl group in position 4, a 4-chloro-3-methylphenyl group, a 5-chloro-2-thienyl group or a cyclohexyl group,
and their salts,
but especially the connections

• (1) 1- (4-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
• (2) 1- (4-Chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine
• (3) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine
• (4) 1- (4-Chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
• (5) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
• (6) 1- (5-Chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
• (7) 1-cyclohexane carbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,
• (8) 4- [4- (2-Oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine
• (9) 1- (4-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
• (10) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine
• (11) 1- (4-Chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine
• (12) 1- (4-Chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine

and their salts.

Manufacturing methods:

• a) Durch Umsetzung von Verbindungen der allgemeinen Formel II,
  
  in der
  m, p, A, W¹, W², X und R⁷ bis R¹⁰ die eingangs erwähnten Bedeutungen besitzen und R¹² eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen bedeutet, mit Verbindungen der allgemeinen Formel III,
  
  in der
  n, Y und R¹ bis R⁶ die eingangs erwähnten Bedeutungen besitzen.
  Die Umsetzungen werden zweckmäßigerweise in einem geeigneten Lösungsmittel, z. B. in einem Alkohol wie Methanol, Ethanol oder Propanol, in einem Ether wie beispielsweise Diethylether, Di-n-propylether, Tetrahydrofuran oder Dioxan, in Dimethylformamid, Dimethylsulfoxid oder in einem Gemisch der vorstehend erwähnten Lösungsmittel, gegebenenfalls in Anwesenheit eines halogenwasserstoffbindenden Mittels wie tertiäre Amine, Natriumcarbonat oder Calciumcarbonat bei einer Temperatur zwischen 0 und 100°C durchgeführt. Vorzugsweise wird die Reaktion jedoch in einem Alkohol wie Methanol oder Ethanol bei einer Temperatur zwischen 20 und 80°C durchgeführt. Vorteilhafterweise werden die Verbindungen der allgemeinen Formel II als Salze, vorzugsweise als Hydrochloride, eingesetzt und die Reaktion in Gegenwart von anorganischen oder organischen Basen, vorzugsweise tertiären organischen Aminen wie Triethylamin oder Ethyldiisopropylamin oder einem Überschuß der Verbindungen der allgemeinen Formel III durchgeführt.
• b) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der n, m, p, A, X, Y und R¹ bis R¹⁰ die eingangs erwähnten Bedeutungen besitzen und W¹ und W² zusammen eine Kohlenstoff-Kohlenstoffbindung bedeuten:
  Umsetzung von Phosphonestern der allgemeinen Formel IV,
  
  in der
  n, Y und R¹ bis R⁸ die eingangs erwähnten Bedeutungen besitzen und R¹³ eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen bedeutet, mit Verbindungen der allgemeinen Formel V,
  
  in der
  m, p, A, X, R⁹ und R¹⁰ die eingangs erwähnten Bedeutungen besitzen.
  Die Umsetzungen werden zweckmäßigerweise in einem geeigneten Lösungsmittel, z. B. in einem Ether wie Diethylether, Di-n-propylether, Tetrahydrofuran oder Dioxan, oder in einem Kohlenwasserstoff wie beispielsweise Benzol, Toluol, n-Hexan oder Cyclohexan, oder in einem Gemisch der vorstehend erwähnten Lösungsmittel, vorzugsweise jedoch in einem Gemisch aus Tetrahydrofuran und n-Hexan oder einem Gemisch aus Tetrahydrofuran und Cyclohexan, durchgeführt. Dabei werden zunächst die Verbindungen der allgemeinen Formel IV bei einer Temperatur zwischen -78 und 20°C mit einer geeigneten Base wie beispielsweise n-Butyllithium, Phenyllithium, Natriumamid, Natriumhydrid oder Lithiumdiisoproylamid in die entsprechenden Phosphonatanionen übergeführt und diese anschließend bei einer Temperatur zwischen -78 und 100°C, vorzugsweise jedoch bei einer Temperatur zwischen -15 und 50°C mit den Verbindungen der allgemeinen Formel V umgesetzt.
  Besitzt eine Verbindung der allgemeinen Formel IV eine Hydroxygruppe, empfiehlt es sich, diese vor Durchführung der Reaktion durch eine geeignete Schutzgruppe wie beispielsweise die Silylgruppe zu schützen und die Schutzgruppe nach beendeter Reaktion wieder abzuspalten. Als Silylierungsreagens eignet sich z. B. Trimethylchlorsilan. Die Abspaltung erfolgt beispielsweise mittels saurer Hydrolyse oder durch Behandeln mit Fluoridionen, z. B. mit Cäsiumfluorid oder Tetrabutylammoniumfluorid.
• c) Durch Umsetzung von Verbindungen der allgemeinen Formel VI,
  
  in der
  n, m, p, W¹, W², Y und R¹ bis R⁹ die eingangs erwähnten Bedeutungen besitzen, mit Verbindungen der allgemeinen Formel VII,
  
  
  
          Z¹ - X - A - R¹⁰   (VII)
  
  
  
  in der
  A, X und R¹⁰ die eingangs erwähnten Bedeutungen besitzen und Z¹ eine reaktive Austrittsgruppe wie z. B. ein Halogenatom, vorzugsweise ein Chloratom, oder die Imidazolidgruppe bedeutet.
  Bedeutet Z¹ ein Halogenatom, werden die Umsetzungen in einem geeigneten inerten Lösungsmittel wie Diethylether, Toluol, Methylenchlorid und dergleichen, vorzugsweise bei Temperaturen zwischen -50°C und 50°C und in Gegenwart eines halogenwasserstoffbindenden Mittels, wie tertiäre Amine, Natriumcarbonat oder Calciumcarbonat, durchgeführt. Dabei können nicht nur die freien Amine der allgemeinen Formel VI eingesetzt werden, sondern auch deren Salze, aus denen in situ die Amine durch geeignete Basen, z. B. tertiäre organische Amine, freigesetzt werden können.
  Bedeutet Z¹ den Imidazolidrest, werden die Umsetzungen vorzugsweise in einem inerten Lösungsmittel, wie Xylol oder Tetrahydrofuran, bei Temperaturen zwischen Raumtemperatur und der Siedetemperatur der Reaktionsmischung durchgeführt.
  Besitzt eine Verbindung der allgemeinen Formel VI eine Hydroxygruppe, kann die Umsetzung so abgewandelt werden, daß zwei Äquivalente der Verbindung der allgemeinen Formel VII verwendet werden und nach beendeter Umsetzung die aus der Hydroxygruppe gebildete Estergruppe wieder verseift wird.
  Die gegebenenfalls anschließende Verseifung einer so gebildeten Estergruppe erfolgt vorzugsweise durch alkalische Hydrolyse in einem wässrigen Lösungsmittel, z.B. in Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser oder Dioxan/Wasser, beispielsweise in Gegenwart einer Alkalibase wie Natriumhydroxid oder Kaliumhydroxid bei Temperaturen zwischen 0 und 100°C.
• d) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der n, m, p, X und R⁷ bis R⁹ wie eingangs erwähnt definiert sind, A eine Einfachbindung oder eine geradkettige oder verzweigte Alkylengruppe mit 1 bis 17 Kohlenstoffatomen, W¹ und W² jeweils ein Wasserstoffatom und Y ein Sauerstoffatom oder die 〉NR¹¹-Gruppe bedeuten, wobei R¹¹ wie eingangs erwähnt definiert ist, R¹ bis R⁶ mit Ausnahme der durch eine Alkylthiogruppe substituierten geradkettigen oder verzweigten Alkylgruppe mit 1 bis 4 Kohlenstoffatomen und R¹⁰ mit Ausnahme der gegebenenfalls durch ein Halogenatom substituierten Thienylgruppe wie eingangs erwähnt definiert sind, wobei A keine Einfachbindung sein kann, wenn X die Sulfonylgruppe und R¹⁰ ein Wasserstoffatom bedeuten:
  Hydrierung einer Verbindung der allgemeinen Formel I',
  
  in der
  n, m, p, X und R⁷ bis R⁹ wie eingangs erwähnt definiert sind, A' eine Einfachbindung oder eine geradkettige oder verzweigte Alkylengruppe mit 1 bis 17 Kohlenstoffatomen, W^1' und W^2' zusammen eine Kohlenstoff-Kohlenstoffbindung und Y' ein Sauerstoffatom oder die 〉NR¹¹-Gruppe bedeuten, wobei R¹¹ wie eingangs erwähnt definiert ist, R¹ bis R⁶ mit Ausnahme der durch eine Alkylthiogruppe substituierten geradkettigen oder verzweigten Alkylgruppe mit 1 bis 4 Kohlenstoffatomen und R¹⁰ mit Ausnahme der gegebenenfalls durch ein Halogenatom substituierten Thienylgruppe wie eingangs erwähnt definiert sind, wobei A keine Einfachbindung sein kann, wenn X die Sulfonylgruppe und R¹⁰ ein Wasserstoffatom bedeuten.
  Die Hydrierung wird in einem geeigneten Lösungsmittel wie in einem Alkohol, beispielsweise in Methanol, Ethanol oder Propanol, in einem Ester, beispielsweise in Ethylacetat, in einem Ether, beispielsweise in Diethylether, Tetrahydrofuran oder Dioxan, oder deren Gemischen mit katalytisch angeregtem Wasserstoff, z.B. mit Wasserstoff in Gegenwart eines Hydrierungskatalysators wie Raney-Nickel, Rhodium, Palladium, Palladium/Kohle, Platin oder Platin/Kohle und einem Wasserstoffdruck von 10 bis 500 psi, vorzugsweise jedoch 50 bis 100 psi, bei Temperaturen zwischen 0 und 100°C, vorzugsweise jedoch bei Raumtemperatur, durchgeführt.
  Bei der vorstehenden Hydrierung kann ein in den Resten R¹ bis R⁶ und R¹⁰ vorhandenes Halogenatom gegebenenfalls durch ein Wasserstoffatom ausgetauscht werden.
• e) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der n, m, p, A, X, W¹, W² und R¹ bis R¹⁰ die eingangs erwähnten Bedeutungen besitzen und Y ein Sauerstoffatom bedeutet:
  Cyclisierung von Verbindungen der allgemeinen Formel VIII,
  
  in der
  n, m, p, A, X, W¹, W² und R¹ bis R¹⁰ wie eingangs erwähnt definiert sind.

The compounds of the general formula I can be prepared by the following methods:

• a) by reacting compounds of the general formula II,
  
  in the
  m, p, A, W¹, W², X and R⁷ to R¹⁰ have the meanings mentioned above and R¹² represents an alkyl group having 1 to 10 carbon atoms, with compounds of the general formula III,
  
  in the
  n, Y and R¹ to R⁶ have the meanings mentioned above.
  The reactions are conveniently carried out in a suitable solvent, e.g. B. in an alcohol such as methanol, ethanol or propanol, in an ether such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane, in dimethylformamide, dimethyl sulfoxide or in a mixture of the aforementioned solvents, optionally in the presence of a hydrogen halide agent such as tertiary Amines, sodium carbonate or calcium carbonate at a temperature between 0 and 100 ° C. However, the reaction is preferably carried out in an alcohol such as methanol or ethanol at a temperature between 20 and 80 ° C. The compounds of the general formula II are advantageously used as salts, preferably as hydrochlorides, and the reaction is carried out in the presence of inorganic or organic bases, preferably tertiary organic amines such as triethylamine or ethyldiisopropylamine or an excess of the compounds of the general formula III.
• b) For the preparation of compounds of the general formula I in which n, m, p, A, X, Y and R¹ to R¹⁰ have the meanings mentioned above and W¹ and W² together mean a carbon-carbon bond:
  Implementation of phosphonic esters of the general formula IV,
  
  in the
  n, Y and R¹ to R⁸ have the meanings mentioned at the outset and R¹³ is an alkyl group having 1 to 10 carbon atoms, with compounds of the general formula V,
  
  in the
  m, p, A, X, R⁹ and R¹⁰ have the meanings mentioned above.
  The reactions are conveniently carried out in a suitable solvent, e.g. B. in an ether such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane, or in a hydrocarbon such as benzene, toluene, n-hexane or cyclohexane, or in a mixture of the solvents mentioned above, but preferably in a mixture of tetrahydrofuran and n-hexane or a mixture of tetrahydrofuran and cyclohexane. The compounds of the general formula IV are first converted into the corresponding phosphonate anions at a temperature between -78 and 20.degree. C. using a suitable base such as, for example, n-butyllithium, phenyllithium, sodium amide, sodium hydride or lithium diisoproylamide, and these are then converted at a temperature between -78 and 100 ° C, but preferably at a temperature between -15 and 50 ° C with the compounds of general formula V.
  If a compound of the general formula IV has a hydroxyl group, it is advisable to protect it before the reaction is carried out with a suitable protective group, such as, for example, the silyl group, and to split off the protective group again after the reaction has ended. As a silylating reagent z. B. trimethylchlorosilane. The secession takes place for example by means of acid hydrolysis or by treatment with fluoride ions, e.g. B. with cesium fluoride or tetrabutylammonium fluoride.
• c) by reacting compounds of the general formula VI,
  
  in the
  n, m, p, W¹, W², Y and R¹ to R⁹ have the meanings mentioned above, with compounds of the general formula VII,
  
  
  
  Z¹ - X - A - R¹⁰ (VII)
  
  
  
  in the
  A, X and R¹⁰ have the meanings mentioned and Z¹ is a reactive leaving group such as. B. is a halogen atom, preferably a chlorine atom, or the imidazolide group.
  If Z 1 represents a halogen atom, the reactions are carried out in a suitable inert solvent such as diethyl ether, toluene, methylene chloride and the like, preferably at temperatures between -50 ° C and 50 ° C and in the presence of a hydrogen-halogen-binding agent such as tertiary amines, sodium carbonate or calcium carbonate . Not only the free amines of the general formula VI can be used, but also their salts, from which in situ the amines through suitable bases, e.g. B. tertiary organic amines can be released.
  If Z¹ is the imidazolide radical, the reactions are preferably carried out in an inert solvent, such as xylene or tetrahydrofuran, at temperatures between room temperature and the boiling point of the reaction mixture.
  If a compound of the general formula VI has a hydroxyl group, the reaction can be modified so that two equivalents of the compound of the general formula VII are used and, after the reaction has ended, the ester group formed from the hydroxyl group is saponified again.
  The optionally subsequent saponification of an ester group thus formed is preferably carried out by alkaline hydrolysis in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, for example in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C.
• d) For the preparation of compounds of general formula I, in which n, m, p, X and R⁷ to R⁹ are defined as mentioned above, A is a single bond or a straight-chain or branched alkylene group having 1 to 17 carbon atoms, W¹ and W² each Hydrogen atom and Y represent an oxygen atom or the〉 NR¹¹ group, where R¹¹ is defined as mentioned at the beginning, R¹ to R⁶ with the exception of the straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted by an alkylthio group and R¹⁰ with the exception of those optionally substituted by a halogen atom Thienyl group are defined as mentioned at the outset, where A cannot be a single bond if X is the sulfonyl group and R¹⁰ is a hydrogen atom:
  Hydrogenation of a compound of general formula I ',
  
  in the
  n, m, p, X and R⁷ to R⁹ are defined as mentioned at the outset, A 'is a single bond or a straight-chain or branched alkylene group having 1 to 17 carbon atoms, W ^1' and W ^{2 '} together are a carbon-carbon bond and Y' is an oxygen atom or the〉 NR¹¹ group, where R¹¹ is defined as mentioned at the outset, R¹ to R⁶ with the exception of the straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted by an alkylthio group and R¹⁰ with the exception of the thienyl group which is optionally substituted by a halogen atom, as mentioned at the beginning are, where A cannot be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom.
  The hydrogenation is carried out in a suitable solvent, such as in an alcohol, for example in methanol, ethanol or propanol, in an ester, for example in ethyl acetate, in an ether, for example in diethyl ether, tetrahydrofuran or dioxane, or mixtures thereof with catalytically excited hydrogen, for example with Hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, rhodium, palladium, palladium / carbon, platinum or platinum / carbon and a hydrogen pressure of 10 to 500 psi, preferably however 50 to 100 psi, at temperatures between 0 and 100 ° C., but preferably at room temperature.
  In the above hydrogenation, a halogen atom present in the radicals R¹ to R⁶ and R¹⁰ can optionally be replaced by a hydrogen atom.
• e) For the preparation of compounds of the general formula I in which n, m, p, A, X, W¹, W² and R¹ to R¹⁰ have the meanings mentioned above and Y is an oxygen atom:
  Cyclization of compounds of general formula VIII,
  
  in the
  n, m, p, A, X, W¹, W² and R¹ to R¹⁰ are defined as mentioned above.

The cyclization is conveniently carried out in a suitable solvent, e.g. B. in diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, methylene chloride, chloroform, benzene, toluene or n-hexane or in a mixture of the aforementioned solvents in the presence of a dehydrating agent such as the combination of dialkyl azodicarboxylic acid and triphenylphosphine or of methyl N- (triethylamoniosulfonyl) carbamate (Burgess reagent) at a temperature between 0 and 150 ° C, preferably at a temperature between 0 and 100 ° C. The use of the Burgess reagent for the preparation of oxazolines is described in Tetrahedron Letters 33 , 907-910 [1992]. Another cyclization method is described in Tetrahedron Letters 33 , 2807-2810 [1992].

The compounds of general formula I prepared by the above processes can be prepared by known methods, e.g. B. Clean and isolate crystallization, distillation or chromatography. They can be converted into their acid addition salts with inorganic or organic acids by methods known per se.

In the compounds of the formula I according to the invention, depending on the nature of the radicals R¹ to R⁶, the carbon atoms associated with these radicals can be in optically active form. The invention encompasses both the pure isomers and the mixtures of the various isomers.

Starting materials:

in der
m, p, A, W¹, W², X und R⁷ bis R¹⁰ wie eingangs erwähnt definiert sind und D eine Cyanogruppe darstellt, durch Umsetzung mit Alkoholen der Formel R¹²OH, wobei R¹² eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen bedeutet, in Gegenwart von Chlorwasserstoff herstellen.The starting compounds of the general formula II can be obtained from compounds of the general formula IX,

in the
m, p, A, W¹, W², X and R⁷ to R¹⁰ are defined as mentioned above and D represents a cyano group, by reaction with alcohols of the formula R¹²OH, where R¹² is an alkyl group having 1 to 10 carbon atoms, in the presence of hydrogen chloride .

in der
R⁷ und R⁸ wie eingangs erwähnt definiert sind, R¹³ eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen und D eine Cyano- oder Alkoxycarbonylgruppe darstellt, mit Ketonen der Formel V,

in der
m, p, A, X, R⁹ und R¹⁰ wie eingangs erwähnt definiert sind, in Gegenwart von Basen wie beispielsweise n-Butyllithium, Phenyllithium, Natriumamid, Natriumhydrid oder Lithiumdiisopropylamid und gegebenenfalls anschließender Hydrierung der so erhaltenen olefinischen Doppelbindung.Compounds of the formula IX in which D represents a cyano or alkoxycarbonyl group are in turn accessible by reacting phosphonic esters of the formula X,

in the
R⁷ and R⁸ are defined as mentioned at the outset, R¹³ represents an alkyl group having 1 to 10 carbon atoms and D represents a cyano or alkoxycarbonyl group, with ketones of the formula V,

in the
m, p, A, X, R⁹ and R¹⁰ are defined as mentioned above, in the presence of bases such as n-butyllithium, phenyllithium, sodium amide, sodium hydride or lithium diisopropylamide and optionally subsequent hydrogenation of the olefinic double bond thus obtained.

in der
m, p und R⁹ wie eingangs erwähnt definiert sind, umgesetzt werden.An alternative method for the preparation of compounds of formula IX, in which m, p, A, W¹, W², X and R⁷ to R¹⁰ are defined as mentioned above and D represents an alkoxycarbonyl or cyano group, is that phosphonic esters of
Formula X, in which R⁷, R⁸ and R¹³ are as defined above and D represents an alkoxycarbonyl or cyano group, with ketones of the formula XI,

in the
m, p and R⁹ are defined as mentioned above, are implemented.

The benzyl radical is then removed, for example by reaction with 1-chloroethyl chloroformate, the urethane thus formed is cleaved with methanol and finally with compounds of the general formula VII,



Z¹ - X - A - R¹⁰ (VII)



in the
A, X and R¹⁰ have the meanings mentioned and Z¹ is a reactive leaving group such as. B. a halogen atom, preferably a chlorine atom, or the imidazolid group means implemented. The olefinic double bond can then, if desired, be hydrogenated.

in der
R⁷ und R⁸ wie eingangs erwähnt definiert sind, D eine Cyano- oder Alkoxycarbonylgruppe darstellt und Hal ein Halogenatom wie beispielsweise ein Chlor- oder Bromatom bedeutet, und Trialkylphosphiten der Formel (R₁₃0)₃P, in der R¹³ wie vorstehend erwähnt definiert ist, darstellen. Eine bevorzugte Variante der Reaktion zur Herstellung von Verbindungen der Formel X, in der R⁸ eine Alkylgruppe bedeutet, besteht darin, zunächst Verbindungen der Formel X herzustellen, in der R⁸ ein Wasserstoffatom bedeutet, und diese anschließend mit einem Alkylierungsmittel der Formel R⁸-Z², in der R⁸ einen wie eingangs definierten Alkylrest und Z² ein Halogenatom wie ein Chlor-, Brom- oder Jodatom oder eine Sulfonyloxygruppe bedeutet, umzusetzen.The phosphonic esters of the formula X can be obtained by an Arbusow reaction from halides of the formula XII,

in the
R⁷ and R⁸ are as defined in the introduction, D represents a cyano or alkoxycarbonyl group and Hal represents a halogen atom such as, for example, a chlorine or bromine atom, and trialkyl phosphites of the formula (R₁₃0) ₃P, in which R¹³ is defined as mentioned above. A preferred variant of the reaction for the preparation of compounds of the formula X, in which R bedeutet is an alkyl group, consists in first preparing compounds of the formula X in which R⁸ is a hydrogen atom, and then with an alkylating agent of the formula R⁸-Z², in which R⁸ is an alkyl radical as defined in the introduction and Z² is a halogen atom such as a chlorine, bromine or iodine atom or a sulfonyloxy group.

The starting compounds of the general formulas III and XII are known from the literature or can be prepared by known methods.

in der
R⁷, R⁸ und R¹² wie eingangs erwähnt definiert sind und R¹³ eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen bedeutet, durch Umsetzung mit Verbindungen der allgemeinen Formel III erhalten.The phosphonic esters of the general formula IV can be obtained from phosphonic esters of the general formula XIII,

in the
R⁷, R⁸ and R¹² are defined as mentioned at the outset and R¹³ is an alkyl group having 1 to 10 carbon atoms, obtained by reaction with compounds of the general formula III.

The phosphonic esters of the formula XIII are obtainable from the phosphonic esters of the formula X, in which D is a cyano group, by reaction with alcohols of the formula R 12 OH, in which R 12 is defined as mentioned above, in the presence of hydrogen chloride.

in der
m, p und R⁹ wie eingangs erwähnt definiert sind, mit Verbindungen der allgemeinen Formel VII erhalten.The compounds of the general formula V are obtained by reacting compounds of the formula XIV,

in the
m, p and R⁹ are defined as mentioned above, obtained with compounds of general formula VII.

in der
m, p und R⁹ wie eingangs erwähnt definiert sind und R¹⁴ die Triphenylmethyl- oder tert.Butyloxycarbonylgruppe bedeutet, in Gegenwart starker Basen wie n-Butyllithium, Phenyllithium, Natriumamid, Natriumhydrid oder Lithiumdiisopropylamid und gegebenenfalls anschließender katalytischer Hydrierung der gebildeten olefinischen Doppelbindung sowie Abspaltung des wie vorstehend definierten Restes R¹⁴ mittels Trifluoressigsäure, wobei im Falle der Triphenylmethylverbindung diese Schutzgruppe gleichzeitig hydrogenolytisch abgespalten werden kann, darstellen.The starting compounds of the general formula VI can be obtained from the phosphonic esters of the general formula IV by reaction with compounds of the general formula XV,

in the
m, p and R⁹ are defined as mentioned at the outset and R¹⁴ is the triphenylmethyl or tert.butyloxycarbonyl group, in the presence of strong bases such as n-butyllithium, phenyllithium, sodium amide, sodium hydride or lithium diisopropylamide and optionally subsequent catalytic hydrogenation of the olefinic double bond formed and cleavage of the like radical R¹⁴ defined above by means of trifluoroacetic acid, in the case of the triphenylmethyl compound this protective group can simultaneously be split off by hydrogenolysis.

in der
R⁹ wie eingangs definiert ist, mit einem Aldehyd der Formel XVII,

in der
R⁷ wie eingangs definiert ist, unter gleichzeitiger Abspaltung des N-Acetylrestes kondensiert wird, anschließend unter Einwirkung von Chlorwasserstoff mit einem Alkohol der Formel R¹²OH, in der R¹² eine Alkylgruppe mit 1 bis 10 Kohlenstoffatomen darstellt, umgesetzt wird und das so erhaltene Zwischenprodukt mit einer Verbindung der Formel III,

in der
n, Y und R¹ bis R⁶ die eingangs erwähnten Bedeutungen besitzen, cyclisiert wird. Danach wird die Amidgruppe beispielsweise mit Lithiumaluminiumhydrid reduziert und, falls gewünscht, die olefinische Doppelbindung hydriert.An alternative method for the preparation of compounds of the general formula VI, in which p is the number O, m the number 1 and R⁸ is a hydrogen atom and n, W¹, W², Y, R¹ to R⁷ and R⁹ are defined as mentioned above, is that first a compound of formula XVI,

in the
R⁹ is as defined in the introduction, with an aldehyde of the formula XVII,

in the
R⁷ is as defined in the introduction, is condensed with simultaneous cleavage of the N-acetyl radical, then under the action of hydrogen chloride with an alcohol of the formula R¹²OH, in which R¹² represents an alkyl group having 1 to 10 carbon atoms, and the intermediate thus obtained is reacted with a compound Formula III,

in the
n, Y and R¹ to R⁶ have the meanings mentioned, is cyclized. The amide group is then reduced, for example with lithium aluminum hydride, and, if desired, the olefinic double bond is hydrogenated.

Starting compounds of the general formula VIII can be obtained from compounds of the general formula IX, in which m, p, W¹, W², X, A and R⁷ to R¹⁰ are defined as mentioned at the beginning and D denotes an alkoxycarbonyl group, by saponification of the alkoxycarbonyl group and reaction of the resultant Carboxylic acid first with N, N'-carbonyldiimidazole and then with compounds of formula III, in which n and R¹ to R⁶ are as defined above and Y represents an oxygen atom.

The compounds of general formula I have interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxisqualen-lanosterol cyclase. Because of their biological properties, they are particularly suitable for the treatment and prophylaxis of hyperlipidemias, in particular hypercholesterolemia, hyperlipoproteinemia and hypertriglyceridemia and the resulting atherosclerotic Vascular changes with their complications such as coronary artery disease, cerebral ischemia, intermittent claudication, gangrene and others.

• gallensäurebindende Harze wie z. B. Cholestyramin, Cholestipol und andere,
• Verbindungen, die die Cholesterolresorption hemmen, wie z. B. Sitosterol und Neomycin,
• Verbindungen, die in die Cholesterolbiosynthese eingreifen, wie z. B. HMG-CoA-Reduktaseinhibitoren wie Lovastatin, Simvastatin, Pravastatin und andere,
• Squalen-Epoxidaseinhibitoren wie beispielsweise NB 598 und analoge Verbindungen sowie
• Squalen-Synthetaseinhibitoren wie beispielsweise Vertreter der Klasse der Isoprenoid-(phosphinylmethyl)phosphonate und Squalestatin.

To treat these diseases, the compounds of the general formula I can either be used alone for monotherapy or in combination with other cholesterol- or lipid-lowering substances, the compounds preferably being administered as an oral formulation, optionally also in the form of suppositories, as a rectal formulation can be. Possible combination partners include:

• Bile acid binding resins such as. B. cholestyramine, cholestipol and others,
• Compounds that inhibit cholesterol absorption, such as B. sitosterol and neomycin,
• Compounds that interfere with cholesterol biosynthesis, such as. B. HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin and others,
• Squalene epoxidase inhibitors such as NB 598 and analogue compounds as well
• Squalene synthetase inhibitors such as representatives of the class of the isoprenoid (phosphinylmethyl) phosphonates and squalestatin.

Further possible combination partners are the class of fibrates, such as clofibrate, bezafibrate, gemfibrozil and others, nicotinic acid, its derivatives and analogues such as, for example, Acipimox and Probucol.

Furthermore, the compounds of general formula I are suitable for the treatment of diseases which are associated with excessive cell proliferation. Cholesterol is an essential cell component and must be used for cell proliferation, i.e. H. Cell division, be present in sufficient quantities. The inhibition of cell proliferation by inhibition of cholesterol biosynthesis is described using the example of smooth muscle cells with the HMG-CoA reductase inhibitor of the mevinoline type lovastatin, as mentioned at the beginning.

Tumor diseases should first be mentioned as examples of diseases which are associated with excessive cell proliferation. In cell culture and in vivo experiments it has been shown that the reduction in serum cholesterol or the intervention in cholesterol biosynthesis by HMG-CoA reductase inhibitors reduces tumor growth (Lancet 339 , 1154-1156 [1992]). The compounds of formula I according to the invention are therefore potentially suitable for the treatment of tumor diseases on account of their cholesterol biosynthesis-inhibiting action. You can use it alone or to support known therapeutic principles.

Hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and keratinization disorders are further examples. The term "psoriasis" used here denotes a hyperproliferative-inflammatory skin disease that changes the regulation mechanism of the skin. In particular, lesions are formed that include primary and secondary changes in epidermal proliferation, inflammatory skin reactions, and the expression of regulatory molecules such as lymphokines and inflammatory factors. Psoriatic skin is characterized morphologically by an increased turnover of epidermal cells, thickened epidermis, abnormal keratinization of inflammatory cell infiltrates into the dermis layer and polymorphonuclear leukocyte infiltration into the epidermis, which causes an increase in the basal cell cycle. Hyperkeratotic and parakeratotic cells are also present. The terms "keratosis", "basal cell carcinomas", "squamous cell carcinomas" and "keratinization disorders" refer to hyperproliferative skin diseases in which the regulation mechanism for the proliferation and differentiation of the skin cells is interrupted.

The compounds of formula I are effective as antagonists of skin hyperproliferation, i.e. H. as agents that inhibit hyperproliferation of human keratinocytes. The compounds are therefore suitable as agents for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratinization disorders and keratosis. For the treatment of these diseases, the compounds of the formula I can be administered either orally or topically, where they can be used either alone in the form of monotherapy or in combination with known active ingredients.

Also to be mentioned are surgical measures such as PTCA (percutaneous transluminal coronary angioplasty) or bypass operations hyperproliferative vascular diseases such as stenoses and vascular occlusions, which are based on the proliferation of smooth muscle cells. As mentioned at the outset, this cell proliferation is known to be caused by HMG-CoA reductase inhibitors of the mevinoline type, such as lovastatin, suppress. Because of their inhibitory effect on cholesterol biosynthesis, the compounds of general formula I are also suitable for the treatment and prophylaxis of these diseases, they either alone or in combination with known active ingredients, such as. B. intravenously administered heparin, preferably in oral application.

Another possible use of the compounds of general formula I according to the invention is the prophylaxis and treatment of gallstone disorders. The formation of gallstones is triggered by the fact that the cholesterol concentration in the bile exceeds the maximum solubility of the cholesterol in the bile, which leads to the precipitation of the cholesterol in the form of gallstones. Lipid-lowering agents from the fibrate class lead to an increased excretion of neutral steroids via the bile and increase the tendency to form gallstones.

In contrast, cholesterol biosynthesis inhibitors such as lovastatin or pravastatin do not lead to increased gallstone formation, on the contrary they can reduce the cholesterol concentration in the bile and thus reduce the so-called lithogenic index, a measure of the likelihood of gallstone formation. This is described in Gut 31 , 348-350 [1990] and in Z. Gastroenterol. 29 , 242-245 [1991].

In addition, in Gastroenterology 102 , No. 4, Pt. 2, A 319 [1992] described the effectiveness of lovastatin in the dissolution of gallstones, particularly in combination with ursodeoxycholic acid. Because of their mode of action, the compounds of the general formula I are therefore also important for the prophylaxis and treatment of gallstone disorders. They can be used either alone or in combination with known therapies, such as treatment with ursodeoxycholic acid or shock wave lithotripsy, preferably in oral application.

Finally, the compounds of general formula I are suitable for the therapy of infections by pathogenic fungi such as. B. Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and other. As already mentioned at the beginning, the end product of sterol biosynthesis in the fungal organism is not cholesterol, but the ergosterol essential for the integrity and function of the fungal cell membranes. The inhibition of ergosterol biosynthesis therefore leads to growth disorders and possibly to the fungal organisms being killed.

For the treatment of mycoses, the compounds of general formula I can be administered either orally or topically. They can be used either alone or in combination with known antifungal agents, in particular those which intervene in other stages of sterol biosynthesis, such as, for example, the squalene epoxidase inhibitors terbinafine and naftifine or the lanosterol-14α-demethylase inhibitors of the azole type, such as, for example, ketoconazole and fluconazole.

Another possible use of the compounds of the general formula I relates to their use in poultry farming. The reduction in the cholesterol content of eggs by administration of the HMG-CoA reductase inhibitor lovastatin to laying hens has been described (FASEB Journal 4 , A 533, Abstracts 1543 [1990]). The production of low-cholesterol eggs is of interest because the cholesterol load of the body can be reduced by eggs with a reduced cholesterol content without changing dietary habits. Because of their inhibitory effect on cholesterol biosynthesis, the compounds of general formula I can also be used in poultry farming to produce low-cholesterol eggs, the substances preferably being administered as an additive to the feed.

The biological activity of compounds of the general formula I was determined using the following methods:

I. Measurement of the inhibition of the ¹⁴C acetate incorporation into the steroids precipitated with digitonin: Method:

Human hepatoma cells (HEP-G2) are stimulated after 3 days of cultivation for 16 hours in a cholesterol-free medium. The substances to be tested (dissolved in dimethyl sulfoxide, final concentration 0.1%) are added during this stimulation phase. Subsequently, after adding 200 »mol / l of 2 -11 C acetate for a further two hours at 37 ° C in the incubator.

After detachment of the cells and saponification of the sterol esters, sterols with digitonin are precipitated after extraction. The ¹⁴C-acetate built into digitone-inconsistent sterols is determined by scintillation measurement.

A =

1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)-benzyliden]piperidin

B =

1-(4-Chlorbenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzyliden]piperidin

C =

4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(4-trifluormethylbenzoyl)piperidin

D =

1-(4-Chlor-3-methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

E =

1-(4-Fluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

F =

1-(5-Chlor-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

G =

1-Cyclohexancarbonyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin.

H =

4-[4-(2-Oxazolin-2-yl)benzyl]-1-(4-trifluormethylbenzoyl)piperidin

I =

1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)-benzyl]piperidin

K =

1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl)-benzyliden]pyrrolidin

L =

1-(4-Chlorbenzoyl)-4-[2-fluor-4-(2-oxazolin-2-yl)benzyliden]piperidin

M =

1-(4-Chlorbenzoyl)-4-[3-methyl-4-(2-oxazolin-2-yl)benzyliden]piperidin

N =

1-(4-Chlorbenzolsulfonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

O =

1-(4-Chlorbenzolsulfonyl)-4-[4-(2-imidazolin-2-yl)benzyliden]piperidin

P =

1-(4-Chlorbenzoyl)-4-[4-(2-thiazolin-2-yl)benzyl]piperidin

Q =

1-(4-Chlorbenzoyl)-4-[4-(S-5-methyl-2-oxazolin-2-yl)benzyliden]piperidin

R =

1-(4-Chlorbenzoyl)-4-[4-(R-4-methyl-2-oxazolin-2-yl)benzyliden]piperidin

S =

1-(4-Chlorbenzoyl)-4-[4-(5-phenyl-2-oxazolin-2-yl)benzyliden]piperidin

T =

1-(4-Chlorbenzoyl)-4-[4-(5-diethylaminomethyl-2-oxazolin-2-yl)benzyliden]piperidin

U =

1-(4-Chlorbenzoyl)-4-[4-(4-hydroxmethyl-2-oxazolin-2-yl)benzyliden]piperidin

V =

4-[4-(S-4-Benzyl-2-oxazolin-2-yl)benzyliden]-1-(4-chlorbenzoyl)piperidin

W =

1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)-α-methylbenzyliden]piperidin

X =

1-(5-Chlor-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

Y =

1-(4-Cyanobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

Z =

4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(pentafluorbenzoyl)piperidin

AA =

1-Benzoyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AB =

1-(4-tert.-Butylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AC =

1-(4-Methoxybenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AD =

1-(4-Brombenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AE =

1-(4-Nitrobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AF =

1-(4-Chlorphenylacetyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

AG =

1-(1-Naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin

Die Prozentwerte, um die die obigen Verbindungen den ¹⁴C-Acetat-Einbau hemmen, sind in der folgenden Tabelle angegeben:

The investigation of the inhibitory effect was carried out at test concentrations of 10⁻⁷ mol / l and 10⁻⁸ mol / l. The test results of the following compounds A to AG of the general formula I are given by way of example at these test concentrations:

A =

1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

B =

1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine

C =

4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine

D =

1- (4-chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

E =

1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

F =

1- (5-Chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

G =

1-Cyclohexanecarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine.

H =

4- [4- (2-Oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine

I =

1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine

K =

1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine

L =

1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine

M =

1- (4-chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine

N =

1- (4-chlorobenzenesulfonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

O =

1- (4-chlorobenzenesulfonyl) -4- [4- (2-imidazolin-2-yl) benzylidene] piperidine

P =

1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzyl] piperidine

Q =

1- (4-chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine

R =

1- (4-chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine

S =

1- (4-chlorobenzoyl) -4- [4- (5-phenyl-2-oxazolin-2-yl) benzylidene] piperidine

T =

1- (4-chlorobenzoyl) -4- [4- (5-diethylaminomethyl-2-oxazolin-2-yl) benzylidene] piperidine

U =

1- (4-chlorobenzoyl) -4- [4- (4-hydroxmethyl-2-oxazolin-2-yl) benzylidene] piperidine

V =

4- [4- (S-4-Benzyl-2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine

W =

1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) -α-methylbenzylidene] piperidine

X =

1- (5-Chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

Y =

1- (4-Cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

Z =

4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (pentafluorobenzoyl) piperidine

AA =

1-Benzoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AB =

1- (4-tert-Butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AC =

1- (4-methoxybenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AD =

1- (4-bromobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AE =

1- (4-nitrobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AF =

1- (4-chlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AG =

1- (1-Naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

The percentages by which the above compounds inhibit ¹⁴C acetate incorporation are given in the following table:

As mentioned at the beginning, isolated inhibitors of the enzyme 2,3-epoxysqualen-lanosterol cyclase are described in the literature, but these differ very structurally from the compounds of the formula I according to the invention. The compounds structurally most closely related to the compounds of general formula I are described in EP 0 468 457 A1. For comparison, example 1 of this publication was therefore tested according to the determination method described above in test concentrations of 10⁻⁵ mol / l and 10⁻⁶ mol / l. The inhibition values of 41% and 13% found, respectively, show that these compounds are clearly inferior to the compounds of general formula I according to the invention.

II. Measurement of the in vivo effect on the rat after oral administration

The inhibition of the enzyme 2,3-epoxisqualen-lanosterol cyclase causes an increase in the 2,3-epoxis agony levels in the liver and plasma. The amount of 2,3-epoxy torment formed therefore serves as a direct measure of the potency of the whole animal. The determination is carried out according to the following method:
Male Wistar rats (160-190 g body weight) are given the test substance suspended in 1.5% aqueous methyl cellulose via a pharyngeal tube. 5 hours after application, blood is extracted retroorbitally from the venous plexus. Plasma is worked up according to the method of Bligh and Dyer (Canad. J. Biochem. Physiol. 37 , 912, [1959]), cleaned over a guard column and then analyzed by HPLC. The peaks obtained are identified and quantified using calibration substances. An internal standard is used to check the reproducibility of the results.

The investigations were carried out with concentrations of 0.1 and 1.0 mg / kg. The following table shows an example of the results for substances A to M mentioned above:
2,3-Epoxisqualen concentration (»g / ml) in plasma (rat) mg / kg 0.1 1.0 A 0.71 3.75 B 0.46 3.14 C. 0.91 5.90 D 0.78 3.35 E 0.67 6.09 F 0.00 2.00 G 0.36 0.31 H 1.70 9.15 I. 3.41 8.41 K 0.0 4.14 L 0.44 6.46 M 0.78 6.53

In the control animals, no measurable 2,3-epoxis agony levels occur under the test conditions.

None of the inhibitors of the enzyme 2,3-epoxysqualen-lanosterol cyclase described in the literature has hitherto been described as inhibiting cholesterol biosynthesis in whole animals.

III. Lipid lowering on the normolipemic golden hamster

Male golden hamsters are ad lib for 12 days. fed with cholesterol-free hamster diet. The substance to be tested is mixed into the feed in concentrations of 0.01 to 0.10%. At the end of the test period, the total cholesterol, the HDL fraction and the VLDL + LDL fraction are determined according to standard methods, a control group fed without test substance being used for comparison.

The lipid-lowering activity of compound A mentioned above was tested. The result is summarized in the following table: concentration Total cholesterol VLDL + LDL HDL 0.01% -19.8% -25.0% -12.4% 0.03% -26.3% -31.2% -17.5% 0.10% -25.8% -36.6% -13.9%

IV. Determination of the lithogenic index on the normolipemic golden hamster

The lithogenic index is a measure of the tendency to form gallstones and is defined as the quotient of the maximum equilibrium solubility of the cholesterol at the present bile acid and phospholipid concentration and the current cholesterol content in mol%. It was determined using the Carey and Small method described in J. Clin. Investigious. 61 , "998-1026 [1978]. The higher the lithogenic index, the higher the likelihood of gallstone formation. The determination of the lithogenic index was carried out as follows:
Male golden hamsters are ad lib for 20 days. fed with cholesterol-free hamster diet. The substance to be tested is mixed into the feed in concentrations of 0.01 to 0.1%. At the end of the test period, total cholesterol, the HDL fraction and the VLDL + LDL fraction in the serum and the bile acids, the cholesterol and the phospholipids in the bile are determined by standard methods.

The compound A described above was tested. The percentage decrease in the lithogenic index was determined in comparison with the control. The result is summarized in the following table. concentration lithogenic index 0.01% -24% 0.03% -10% (ns) 0.1% -28% ns = not significant

V. Inhibition of cell proliferation

Normal human epidermal keratinocytes (NHEK) are grown in keratinocyte growth medium (Gibco) in a humidified, 5% CO₂-containing atmosphere under sterile conditions. Third passage cells are seeded at a density of 12000 cells / ml.

After 24 hours, the test substance is added to the medium and the number of cells is determined after a further 48 hours. The Results were calculated compared to a control and are given as a percentage decrease in cell numbers.

The proliferation-inhibiting effect of compound A mentioned above was tested in comparison with simvastatin in concentrations of 10⁻⁶ to 10⁻¹⁰ mol / l.

The result is summarized in the following table: 10⁻⁶ 10⁻⁷ 10⁻⁸ 10⁻⁹ 10⁻¹⁰ A -72% -73% -70% -48% -16 Simvastatin -68% -51% -20% -21% - 7th

VI. Determination of the fungistatic effect

The fungistatic effect was determined using the serial dilution test (microtiter system). Sabouraud broth served as the nutrient medium. The inoculum was approx. 10⁴ to 10⁵ CFU / ml (CFU = colony-forming units); the incubation time was 2 to 4 days at 26 ° C.

The minimum inhibitory concentration (MIC), i.e. H. the lowest concentration that no longer allowed visible growth and the lowest concentration at which the test germ grew less than a control.

Compound I mentioned above was tested. The results are shown in the following table. MIC »g / ml Decrease in growth »g / ml Candida albicans ATCC 10231 128 64 Rhodotorula rubra 49 128 32 Sacc. carlsbergensis ATCC 9080 128 64 Aspergillus niger ATCC 16404 > 1024 128 Trichophyton mentagrophytes ATCC 9129 512 Penicillium notatum CBS 19746 128 64

Compounds A to I were found to be non-toxic in the curative dosage. For example, compounds A, H and I showed no toxic effects on the mouse after oral administration of 100 mg / kg, once a day for 4 days.

For pharmaceutical use, the compounds of general formula I can be incorporated in a manner known per se into the customary pharmaceutical preparation forms for oral, rectal and topical administration.

Formulations for oral administration include, for example, tablets, dragees and capsules; suppositories are preferred for rectal administration. The daily dose is between 1 and 1200 mg for a person with a body weight of 60 kg, but a daily dose of 5 to 100 mg is preferred for a person with a body weight of 60 kg. The daily dose is preferably divided into 1 to 3 single doses.

When applied topically, the compounds can be in preparations containing about 1 to 1000 mg, in particular 10 to 300 mg Containing active ingredient per day. The daily dose is preferably divided into 1 to 3 single doses.

Topical formulations include gels, creams, lotions, ointments, powders, aerosols and other conventional formulations for the application of medicinal products to the skin. The amount of active ingredient for topical use is 1 to 50 mg per gram of formulation, but preferably 5 to 20 mg per gram of formulation. In addition to application to the skin, the topical formulations of the present invention can also be used in the treatment of mucous membranes that are amenable to topical treatment. For example, the topical formulations can be applied to the mucous membranes of the mouth, lower colon and others.

For use in poultry farming for the production of low-cholesterol eggs, the active compounds of the general formula I are administered to the animals according to the customary methods as an additive to suitable feed. The concentration of the active substances in the finished feed is normally 0.01 to 1%, but preferably 0.05 to 0.5%.

The active ingredients can be added to the feed as such. For example, in addition to the active ingredient and, if appropriate, a conventional vitamin-mineral mixture, the feeds according to the invention for laying hens contain, for example, corn, soybean meal, meat meal, feed fat and soybean oil. One of the compounds of the formula I mentioned at the outset is added to this feed as an active ingredient in a concentration of 0.01 to 1%, but preferably 0.05 to 0.5%.

• a) Aluminiumoxid F-254 (Typ E)
• b) Kieselgel 60 F-254.

The following examples serve to explain the invention in more detail. The stated R _f values were determined on prefabricated panels from E. Merck, Darmstadt, namely on:

• a) Aluminum oxide F-254 (type E)
• b) silica gel 60 F-254.

Examples for the production of the starting materials:

Example A 4-Cyano-benzylphosphonic acid diethyl ester

98 g of 4- (bromomethyl) benzonitrile and 300 ml of triethyl phosphite are heated to 140 ° C. until the reaction starts. The mixture is then heated to reflux at a bath temperature of 150-160 ° C for two hours, the ethyl bromide formed is distilled off, heated to 150 ° C for a further hour and then triethyl phosphite is distilled off in vacuo. The residue is mixed with 250 ml of cyclohexane in an ice bath, the crystals formed are suction filtered and washed with 150 ml of cyclohexane. 125.6 g (99.2% of theory) of the title compound of melting point 41.5-43 ° C. are obtained.

• a) 3-Cyano-benzylphosphonsäurediethylester
  aus 3-(Brommethyl)benzonitril und Triethylphosphit.
  Farbloses Öl.
• b) 4-Methoxycarbonyl-3-methyl-benzylphosphonsäurediethylester
  aus 4-Methoxycarbonyl-3-methyl-benzylbromid (J.Med. Chem. 33, 2437-2451 [1990]) und Triethylphosphit.
  Farbloses Öl.
• c) 2-Fluor-4-methoxycarbonyl-benzylphosphonsäurediethylester
  aus 2-Fluor-4-methoxycarbonyl-benzylbromid (hergestellt aus 3-Fluor-4-methyl-benzoesäuremethylester und Brom in Gegenwart von Benzoylperoxid in Tetrachlorkohlenstoff unter Bestrahlung mit einer 1000 Watt-Wolframlampe) und Triethylphosphit.
  Farbloses Öl.
• d) 2-Brom-4-methoxycarbonyl-benzylphosphonsäurediethylester
  aus 2-Brom-4-methoxycarbonyl-benzylbromid (hergestellt aus 3-Brom-4-methyl-benzoesäuremethylester und Brom in Gegenwart von Benzoylperoxid in Tetrachlorkohlenstoff unter Bestrahlung mit einer 1000 Watt-Wolframlampe) und Triethylphosphit.
  Farbloses Öl.
• e) 2-Methoxy-4-methoxycarbonyl-benzylphosphonsäurediethylester
  aus 2-Methoxy-4-methyl-benzylbromid (hergestellt aus 3-Methoxy-4-methyl-benzoesäuremethylester und Brom in Gegenwart von Benzoylperoxid in Tetrachlorkohlenstoff unter Bestrahlung mit einer 1000 Watt-Wolframlampe) und Triethylphosphit.
  Farbloses Öl.

In the same way was obtained:

• a) 3-Cyano-benzylphosphonic acid diethyl ester
  from 3- (bromomethyl) benzonitrile and triethyl phosphite.
  Colorless oil.
• b) 4-methoxycarbonyl-3-methyl-benzylphosphonic acid diethyl ester
  from 4-methoxycarbonyl-3-methyl-benzyl bromide (J.Med. Chem. 33 , 2437-2451 [1990]) and triethyl phosphite.
  Colorless oil.
• c) 2-fluoro-4-methoxycarbonyl-benzylphosphonic acid diethyl ester
  from 2-fluoro-4-methoxycarbonyl-benzyl bromide (made from methyl 3-fluoro-4-methyl-benzoate and bromine in the presence of benzoyl peroxide in carbon tetrachloride under irradiation with a 1000 watt tungsten lamp) and triethyl phosphite.
  Colorless oil.
• d) 2-bromo-4-methoxycarbonyl-benzylphosphonic acid diethyl ester
  from 2-bromo-4-methoxycarbonyl-benzyl bromide (prepared from 3-bromo-4-methyl-benzoic acid methyl ester and bromine in the presence of benzoyl peroxide in carbon tetrachloride under irradiation with a 1000 watt tungsten lamp) and triethyl phosphite.
  Colorless oil.
• e) 2-methoxy-4-methoxycarbonyl-benzylphosphonic acid diethyl ester
  from 2-methoxy-4-methyl-benzyl bromide (prepared from methyl 3-methoxy-4-methyl-benzoate and bromine in the presence of benzoyl peroxide in carbon tetrachloride under irradiation with a 1000 watt tungsten lamp) and triethyl phosphite.
  Colorless oil.

Example B 1- (4-Cyanophenyl) ethylphosphonic acid diethyl ester

18.7 ml of a 1.6 M solution of n-butyllithium in n-hexane are added dropwise to a solution of 7.5 g of diethyl 4-cyano-benzylphosphonate in 60 ml of tetrahydrofuran at -50 ° C., while stirring, followed by 25 minutes at -40 ° C. and then 4.7 g of methyl iodide in 20 ml of tetrahydrofuran were added dropwise at -40 ° C. After stirring overnight at room temperature evaporated, taken up in ethyl acetate, washed with water, the organic phase dried and evaporated. After purification by column chromatography on silica gel (petroleum ether / 2-propanol = 6: 1 to 2: 1, v: v), 5.7 g of the title compound are obtained as a colorless oil.
R _f value: 0.52 (silica gel, petroleum ether / 2-propanol = 3: 1, v: v).

Example C N- (4-chlorobenzoyl) -4-piperidone

87.5 g of 4-chlorobenzoyl chloride and a solution of 276 g of potassium carbonate in 552 ml of water cooled to 5 ° C. are successively added to a suspension of 80.6 g of powdered 4-piperidone hydrochloride hydrate in 1 liter of tetrahydrofuran with stirring. The stirring is continued for 45 minutes at room temperature. The organic phase is then separated off, the aqueous phase is extracted twice more with ethyl acetate, the organic phases are combined, dried and evaporated. The residue is dissolved in ethyl acetate and petroleum ether is added. 88.6 g of the title compound of melting point 61-63 ° C. are obtained.

• a) N-(4-Chlorbenzolsulfonyl)-4-piperidon
  aus 4-Piperidon-hydrochloridhydrat und 4-Chlorbenzolsulfochlorid.
  Schmelzpunkt: 158-160°C.
• b) N-(4-Methylbenzoyl)-4-piperidon
  aus 4-Methylbenzoylchlorid und 4-Piperidon-hydrochloridhydrat.
  Farbloses Harz.
• c) N-(4-Dihydrocinnamoyl)-4-piperidon
  aus 4-Dihydrozimtsäurechlorid und 4-Piperidon-hydrochloridhydrat.
  Farblose Kristalle.
• d) N-(4-Chlorcinnamoyl)-4-piperidon
  aus 4-Chlorzimtsäurechlorid und 4-Piperidon-hydrochloridhydrat.
  Farbloses Harz.
• e) N-Hexanoyl-4-piperidon
  aus Hexansäurechlorid und 4-Piperidon-hydrochloridhydrat.
  Farbloses Öl.
• f) N-Pivaloyl-4-piperidon.
  aus Pivaloylchlorid und 4-Piperidon-hydrochloridhydrat. Farblose Kristalle.
• g) N-Cyclohexancarbonyl-4-piperidon
  aus Cyclohexancarbonsäurechlorid und 4-Piperidon-hydrochloridhydrat.
  Farblose Kristalle.

The following were obtained in the same way:

• a) N- (4-Chlorobenzenesulfonyl) -4-piperidone
  from 4-piperidone hydrochloride hydrate and 4-chlorobenzenesulfochloride.
  Melting point: 158-160 ° C.
• b) N- (4-methylbenzoyl) -4-piperidone
  from 4-methylbenzoyl chloride and 4-piperidone hydrochloride hydrate.
  Colorless resin.
• c) N- (4-Dihydrocinnamoyl) -4-piperidone
  from 4-dihydrocinnamic acid chloride and 4-piperidone hydrochloride hydrate.
  Colorless crystals.
• d) N- (4-chlorocinnamoyl) -4-piperidone
  from 4-chlorocinnamic acid chloride and 4-piperidone hydrochloride hydrate.
  Colorless resin.
• e) N-Hexanoyl-4-piperidone
  from hexanoic acid chloride and 4-piperidone hydrochloride hydrate.
  Colorless oil.
• f) N-pivaloyl-4-piperidone.
  from pivaloyl chloride and 4-piperidone hydrochloride hydrate. Colorless crystals.
• g) N-Cyclohexane carbonyl-4-piperidone
  from cyclohexane carboxylic acid chloride and 4-piperidone hydrochloride hydrate.
  Colorless crystals.

Example D 1- (4-chlorobenzoyl) -4- (4-cyano-benzylidene) piperidine

7.6 g of diethyl 4-cyano-benzylphosphonate in 50 are added to a solution of lithium diisopropylamide prepared from 3.34 g of diisopropylamine in 20 ml of tetrahydrofuran and 19 ml of a 1.6 M solution of n-butyllithium in n-hexane at -50 ° C. ml of tetrahydrofuran were added dropwise. After stirring at this temperature for 20 minutes, a solution of 7.13 g of N- (4-chlorobenzoyl) -4-piperidone is added dropwise. The mixture is allowed to warm to room temperature, poured onto ice after a further two hours and extracted with ethyl acetate. The organic phase is dried and evaporated. After recrystallization from ethyl acetate, 7.6 g of the title compound of melting point 134-135.5 ° C. are obtained.

• a) 1-(4-Chlorbenzoyl)-4-(3-cyano-benzyliden)piperidin
  aus 3-Cyano-benzylphosphonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Farbloser Schaum.
• b) 1-(4-Chlorbenzolsulfonyl)-4-(4-cyano-benzyliden)piperidin
  aus 4-Cyano-benzylphosphonsäurediethylester und N-(4-Chlorbenzolsulfonyl)-4-piperidon.
  Schmelzpunkt: 129-130°C.
• c) 1-(4-Chlorbenzoyl)-4-(4-cyano-α-methyl-benzyliden)piperidin
  aus 1-(4-Cyanophenyl)ethylphosphonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Schmelzpunkt: 134°C.
• d) 1-Benzyl-3-(4-cyano-benzyliden)piperidin
  aus 4-Cyano-benzylphosphonsäurediethylester und N-Benzyl-3-piperidon.
  Schmelzpunkt: 113°C.
• e) 1-(4-Chlorbenzoyl)-4-(4-methoxycarbonyl-3-methyl-benzyliden)piperidin
  aus 4-Methoxycarbonyl-3-methyl-benzylphoshonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Schmelzpunkt: 142-144°C.
• f) 1-(4-Chlorbenzoyl)-4-(2-fluor-4-methoxycarbonyl-benzyliden)piperidin
  aus 2-Fluor-4-methoxycarbonyl-benzylphosphonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Schmelzpunkt: 110-112°C.
• g) 4-(2-Brom-4-methoxycarbonyl-benzyliden)-1-(4-chlorbenzoyl)piperidin
  aus 2-Brom-4-methoxycarbonyl-benzylphosphonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Schmelzpunkt: 140-142°C.
• h) 1-(4-Chlorbenzoyl)-4-(2-methoxy-4-methoxycarbonyl-benzyliden)piperidin
  aus 2-Methoxy-4-methoxycarbonyl-benzylphosphonsäurediethylester und N-(4-Chlorbenzoyl)-4-piperidon.
  Farbloses Öl.

The following were obtained in the same way:

• a) 1- (4-Chlorobenzoyl) -4- (3-cyano-benzylidene) piperidine
  from 3-cyano-benzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.
  Colorless foam.
• b) 1- (4-chlorobenzenesulfonyl) -4- (4-cyano-benzylidene) piperidine
  from 4-cyano-benzylphosphonic acid diethyl ester and N- (4-chlorobenzenesulfonyl) -4-piperidone.
  Melting point: 129-130 ° C.
• c) 1- (4-chlorobenzoyl) -4- (4-cyano-α-methyl-benzylidene) piperidine
  from 1- (4-cyanophenyl) ethylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.
  Melting point: 134 ° C.
• d) 1-benzyl-3- (4-cyano-benzylidene) piperidine
  from 4-cyano-benzylphosphonic acid diethyl ester and N-benzyl-3-piperidone.
  Melting point: 113 ° C.
• e) 1- (4-chlorobenzoyl) -4- (4-methoxycarbonyl-3-methyl-benzylidene) piperidine
  from 4-methoxycarbonyl-3-methyl-benzylphoshonsäurediethylester and N- (4-chlorobenzoyl) -4-piperidone.
  Melting point: 142-144 ° C.
• f) 1- (4-chlorobenzoyl) -4- (2-fluoro-4-methoxycarbonyl-benzylidene) piperidine
  from 2-fluoro-4-methoxycarbonyl-benzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.
  Melting point: 110-112 ° C.
• g) 4- (2-Bromo-4-methoxycarbonylbenzylidene) -1- (4-chlorobenzoyl) piperidine
  from 2-bromo-4-methoxycarbonyl-benzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.
  Melting point: 140-142 ° C.
• h) 1- (4-chlorobenzoyl) -4- (2-methoxy-4-methoxycarbonyl-benzylidene) piperidine
  from 2-methoxy-4-methoxycarbonyl-benzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.
  Colorless oil.

Example E 1- (4-chlorobenzoyl) -3- (4-cyano-benzylidene) piperidine

1.8 g of 1-chloroethyl chloroformate in 5 ml of methylene chloride are added dropwise at 0 ° C. to 2.9 g of 1-benzyl-3- (4-cyano-benzylidene) piperidine in 20 ml of methylene chloride and the mixture is stirred at 0 ° C. for 30 minutes . After 20 minutes at room temperature, the mixture is evaporated, the residue is taken up in 20 ml of methanol and heated to reflux for 30 minutes. The reaction solution is evaporated, the residue is triturated with 100 ml of ethyl acetate and suction filtered. 1.9 g of 3- (4-cyanobenzylidene) piperidine hydrochloride are obtained as a colorless powder.

This product and 2.1 g of triethylamine are dissolved in 15 ml of methylene chloride and 1.75 g of 4-chlorobenzoyl chloride in 5 ml of methylene chloride are added dropwise at room temperature. After 30 minutes at room temperature, 100 ml of methylene chloride are added, extracted twice with water, dried with anhydrous magnesium sulfate, evaporated and purified by column chromatography (silica gel, ethyl acetate). 1.8 g of the title compound are obtained as colorless crystals with a melting point> 210 ° C.

Example F 1- (4-chlorobenzoyl) -4- (4-cyano-benzyl) piperidine

8.4 g of 1- (4-chlorobenzoyl) -4- (4-cyano-benzylidene) piperidine are hydrogenated in 400 ml of toluene with the addition of 2 g of palladium black for 15 minutes at room temperature (5 bar). After adding 1 g of palladium black, the mixture is hydrogenated for a further 2.5 hours, another 1 g of catalyst is added and the mixture is hydrogenated for another hour. 7.9 g (93.3% of theory) of Title compound as a colorless powder with a melting point of 137-139 ° C.

Example G 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride

40.7 g of hydrogen chloride are introduced into a suspension of 10.8 g of 1- (4-chlorobenzoyl) -4- (4-cyano-benzylidene) piperidine in 70 ml of anhydrous ethanol while cooling with ice. After stirring at room temperature for 16 hours, the solvent is evaporated at a bath temperature of 30 ° C., the residue is redissolved in 35 ml of ethanol and then evaporated again. The residue is triturated with ethyl acetate. 13.2 g of the title compound are obtained as a colorless powder.

• a) 1-(4-Chlorbenzoyl)-4-(3-methoxyimidoyl-benzyliden)piperidin-hydrochlorid
  aus 1-(4-Chlorbenzoyl)-4-(3-cyano-benzyliden)piperidin und Methanol.
  Farbloses Harz.
• b) 1-(4-Chlorbenzolsulfonyl)-4-(4-methoxyimidoyl-benzyliden)piperidin-hydrochlorid
  aus 1-(4-Chlorbenzolsulfonyl)-4-(4-cyano-benzyliden)piperidin und Methanol.
  Farbloses Harz.
• c) 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-α-methyl-benzyliden)piperidin-hydrochlorid
  aus 1-(4-Chlorbenzoyl)-4-(4-cyano-α-methyl-benzyliden)piperidin und Ethanol.
  Farbloser Schaum.
• d) 1-(4-Chlorbenzoyl)-3-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid
  aus 1-(4-Chlorbenzoyl)-3-(4-cyano-benzyliden)piperidin.
  Farblose Kristalle.
• e) 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid
  aus 1-(4-Chlorbenzoyl)-4-(4-cyano-benzyl)piperidin.
  Schmelzpunkt: 236°C.

The following were obtained in the same way:

• a) 1- (4-Chlorobenzoyl) -4- (3-methoxyimidoyl-benzylidene) piperidine hydrochloride
  from 1- (4-chlorobenzoyl) -4- (3-cyano-benzylidene) piperidine and methanol.
  Colorless resin.
• b) 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride
  from 1- (4-chlorobenzenesulfonyl) -4- (4-cyano-benzylidene) piperidine and methanol.
  Colorless resin.
• c) 1- (4-Chlorobenzoyl) -4- (4-ethoxyimidoyl-α-methyl-benzylidene) piperidine hydrochloride
  from 1- (4-chlorobenzoyl) -4- (4-cyano-α-methyl-benzylidene) piperidine and ethanol.
  Colorless foam.
• d) 1- (4-chlorobenzoyl) -3- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride
  from 1- (4-chlorobenzoyl) -3- (4-cyano-benzylidene) piperidine.
  Colorless crystals.
• e) 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride
  from 1- (4-chlorobenzoyl) -4- (4-cyano-benzyl) piperidine.
  Melting point: 236 ° C.

Example H 4-Ethoxyimidoyl-benzylphosphonic acid diethyl ester hydrochloride

5.6 g of diethyl 4-cyano-benzylphosphonate and 24 g of hydrogen chloride in 35 ml of anhydrous ethanol are stirred at room temperature for 17 hours. The reaction solution is then evaporated and the residue is evaporated to dryness twice after the addition of ethanol. The colorless crystals obtained are reacted further without purification.

Example I 4- (2-Oxazolin-2-yl) benzylphosphonic acid diethyl ester

The product obtained in Example H is dissolved in 50 ml of ethanol. After adding 1.8 g of ethanolamine and 4.1 g of triethylamine, the reaction solution is heated to reflux for two hours, then evaporated at 50 ° C. and the residue is dissolved in 100 ml of ethyl acetate. The solution is washed three times with water, dried and evaporated. 4.2 g of the title compound of melting point 65 ° C. are obtained.

Example K 4- [4- (2-Oxazolin-2-yl) benzylidene] -1-tritylpiperidine

To 2.97 g of diethyl 4- (2-oxazolin-2-yl) benzylphosphonate, 6.25 ml of a 1.6 M solution of n-butyllithium in hexane are added at -60 ° C. and 3.4 g of N after stirring for 20 minutes -Trityl-4-piperidone (made from 4-piperidone hydrochloride hydrate and trityl chloride) added dropwise in 20 ml of tetrahydrofuran. The mixture is stirred at -60 ° C for 25 minutes. The reaction solution is then allowed to warm to room temperature and stirred at this temperature for a further 1.5 hours. The reaction solution is then stirred into 150 ml of ice water, extracted three times with 150 ml of ethyl acetate, the organic phase is dried and evaporated. The residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1: 1, v: v). 1.7 g of the title compound of melting point 110-115 ° C. are obtained.

• a) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-trityl-hexahydroazepin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und 1-Trityl-hexahydroazepin-4-on (hergestellt aus Hexahydroazepin-4-on und Tritylchlorid).
  Farbloser Schaum.
  R_f-Wert: 0,40 (Kieselgel; Petrolether/Essigsäureethylester = 1:1, v:v).
• b) 1-tert.Butyloxycarbonyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-tert.Butyloxycarbonyl-4-piperidon (hergestellt aus 4-Piperidon-hydrochloridhydrat und Pyrokohlensäure-di-tert.-butylester.
  Schmelzpunkt: 74°C.

The following was shown analogously:

• a) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1-trityl-hexahydroazepine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and 1-trityl-hexahydroazepin-4-one (made from hexahydroazepin-4-one and trityl chloride).
  Colorless foam.
  R _f value: 0.40 (silica gel; petroleum ether / ethyl acetate = 1: 1, v: v).
• b) 1-tert-Butyloxycarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-tert-butyloxycarbonyl-4-piperidone (made from 4-piperidone hydrochloride hydrate and pyrocarbonate di-tert-butyl ester.
  Melting point: 74 ° C.

Example L 1-tert-butyloxycarbonyl-4- [4- (2-oxazolin-2-yl) benzyl) piperidine

2.4 g (7 mmol) of 1-tert-butyloxycarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine, dissolved in 70 ml of anhydrous ethanol and 20 ml of ethyl acetate, are in the presence of 2.5 g Palladium-carbon (10%) catalytically hydrogenated (room temperature, 20 minutes, hydrogen pressure 50 psi). The catalyst is suctioned off, the filtrate is evaporated and the residue is reacted further without purification.

Example M 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

1.0 g of 4- [4- (2-oxazolin-2-yl) benzylidene] -1-tritylpiperidine in 20 ml of methylene chloride is slowly mixed with 2 ml of trifluoroacetic acid at -10 ° C. After stirring for one hour at -10 ° C., the reaction mixture is poured into 150 ml of ice water and immediately adjusted to pH 11.5 with 6N sodium hydroxide solution. After stirring for 10 minutes, the mixture is extracted twice with 150 ml of ether each time, the combined organic phases are washed, dried and evaporated. The residue is purified by column chromatography on aluminum oxide (methylene chloride / methanol = 40: 1, v: v). 340 mg of the title compound of melting point 126 ° C. are obtained.

• a) 4-[4-(2-Oxazolin-2-yl)benzyliden]hexahydroazepin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-trityl-hexahydroazepin und Trifluoressigsäure.
  Schmelzpunkt: sintert ab 46°C.
• b) 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin
  aus 1-tert.Butyloxycarbonyl-4-[4-(2-oxazolin-2-yl)benzyl]piperidin und Trifluoressigsäure.
  Schmelzpunkt: 110°C.

In the same way was obtained:

• a) 4- [4- (2-Oxazolin-2-yl) benzylidene] hexahydroazepine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] -1-trityl-hexahydroazepine and trifluoroacetic acid.
  Melting point: sinters from 46 ° C.
• b) 4- [4- (2-Oxazolin-2-yl) benzyl] piperidine
  from 1-tert-butyloxycarbonyl-4- [4- (2-oxazolin-2-yl) benzyl] piperidine and trifluoroacetic acid.
  Melting point: 110 ° C.

Example N 3- [4- (2-Oxazolin-2-yl) benzylidene] pyrrolidine

To a suspension of 5.36 g sodium hydride (55% in oil) in 50 ml of tetrahydrofuran, a solution of 5.0 g of N-acetyl-2-pyrrolidone and 5.17 g of 4-cyano-benzaldehyde in 50 ml of tetrahydrofuran is added dropwise at 5-10 ° C. and then stirred at 0 ° C. for one hour. Excess sodium hydride is destroyed by adding a little methanol, the reaction mixture is poured onto ice and neutralized with glacial acetic acid. The precipitate is filtered off, dissolved in a methylene chloride-methanol mixture, dried and concentrated. The residue is triturated with ether and suction filtered. 1.4 g of 3- (4-cyano-benzylidene) -2-pyrrolidone are obtained as a colorless powder with a melting point of 260 ° C.

1.36 g of this product are suspended in 30 ml of methanol. About 10 g of hydrogen chloride are introduced with ice cooling, then the mixture is stirred at room temperature for 20 hours and left to stand at room temperature for two days. After concentration, the residue is taken up in 40 ml of ethanol, 0.68 g of ethanolamine and 1.52 g of triethylamine are added, the mixture is heated to reflux for two hours and then concentrated. The residue is triturated with a water / ethyl acetate mixture and the precipitate is then filtered off and dried. 1.5 g of (3- [4- (2-oxazolin-2-yl) benzylidene] -2-pyrrolidone of melting point 258-262 ° C. are obtained.

152 mg of lithium aluminum hydride are added to 0.49 g of this product in 10 ml of tetrahydrofuran and the mixture is stirred at room temperature for two hours. After adding 0.3 ml of water, the mixture is stirred for half an hour at room temperature and the precipitate is then suction filtered. The title compound obtained is reacted further as a solution.

Example O 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-hydroxyethylaminocarbonyl) benzylidene] piperidine

9.0 g of 1- (4-chlorobenzoyl) -4- [2-fluoro-4-methoxycarbonyl-benzylidene) piperidine in 150 ml of methanol are mixed with a solution of 4.0 g of 84% caustic potash in 100 ml of water and stirred overnight at room temperature. The methanol is evaporated, the residue is mixed with water while cooling and acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water and dried in vacuo. 8.6 g (95% of theory) of 4- (4-carboxy-2-fluoro-benzylidene) -1- (4-chlorobenzoyl) piperidine of melting point 170-173 ° C. are obtained.

2.0 g of this product and 0.88 g of N.N'-carbonyldiimidazole in 50 ml of xylene are heated to 60 ° C. for one hour, then 0.32 g of ethanolamine are added and the mixture is stirred at a bath temperature of 160 ° C. for three hours. After evaporation of the solvent, the residue is mixed with water, extracted three times with methylene chloride, the organic extract is dried and evaporated. The residue is purified by column chromatography (silica gel; ethyl acetate / methanol = 10: 0.5, v: v). 0.4 g of the title compound is obtained as a colorless oil.
R _f value: 0.25 (silica gel; ethyl acetate / methanol = 10: 0.5, v: v).

• a) 1-(4-Chlorbenzoyl)-4-[4-(2-hydroxyethylaminocarbonyl)-3-methyl-benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-methoxycarbonyl-3-methyl-benzyliden)piperidin und Ethanolamin.
  Farbloses Öl.
  R_f-Wert: 0,2 (Kieselgel; Essigsäureethylester/Petrolether/Methanol = 10:5:1, v:v:v).
  Die Verseifung des Ausgangsesters wurde in der Siedehitze durchgeführt.
• b) 4-[2-Brom-4-(2-hydroxyethylaminocarbonyl)benzyliden]-1-(4-chlorbenzoyl)piperidin
  aus 4-(2-Brom-4-methoxycarbonyl-benzyliden)-1-(4-chlorbenzoyl)piperidin und Ethanolamin.
  Schmelzpunkt: 90-92°C.
• c) 1-(4-Chlorbenzoyl)-4-[4-(2-hydroxyethylaminocarbonyl)-2-methoxy-benzyliden]piperidin
  aus 4-(2-Methoxy-4-methoxycarbonyl-benzyliden)-1-(4-chlorbenzoyl)piperidin und Ethanolamin.
  Farbloses Öl.

It was represented in the same way:

• a) 1- (4-Chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -3-methylbenzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-methoxycarbonyl-3-methyl-benzylidene) piperidine and ethanolamine.
  Colorless oil.
  R _f value: 0.2 (silica gel; ethyl acetate / petroleum ether / methanol = 10: 5: 1, v: v: v).
  The saponification of the starting ester was carried out at the boiling point.
• b) 4- [2-bromo-4- (2-hydroxyethylaminocarbonyl) benzylidene] -1- (4-chlorobenzoyl) piperidine
  from 4- (2-bromo-4-methoxycarbonyl-benzylidene) -1- (4-chlorobenzoyl) piperidine and ethanolamine.
  Melting point: 90-92 ° C.
• c) 1- (4-Chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -2-methoxybenzylidene] piperidine
  from 4- (2-methoxy-4-methoxycarbonyl-benzylidene) -1- (4-chlorobenzoyl) piperidine and ethanolamine.
  Colorless oil.

Examples for the production of the end products:

example 1 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidi n

13.2 g (0.0315 mol) of 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride are slurried in 59 ml of anhydrous ethanol. After adding 2.64 g (0.042 mol) of ethanolamine and 6.5 g (0.063 mol) of triethylamine, the mixture is heated under reflux for 1.5 hours. After cooling in an ice bath, the product is filtered off with suction and washed with ethanol. 10.4 g (88.6% of theory) of the title compound of melting point 181-183 ° C. are obtained.
1 H NMR Spectrum (200 MHz, CDCl₃); Signals at ppm:
2.3-2.6 (m, 4H), 3.3-3.9 (m, 4H), 4.05 (t, 2H), 4.4 (t, 2H), 6.4 (s, 1H), 7.2 (d, 2H), 7.4 (s, 4H), 7.9 (d, 2H).

The hydrochloride of the title compound was prepared in ethanol with ethereal hydrochloric acid in the cold. It sinters at 69-71 ° C and solidifies again at 80-81 ° C with gas evolution.

• a) 1-(4-Chlorbenzolsulfonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzolsulfonyl)-4-(4-methoxyimidoyl-benzyliden)piperidin-hydrochlorid und Ethanolamin.
  Schmelzpunkt: 191,5-192,5°C.
• b) 1-(4-Chlorbenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und 3-Aminopropanol.
  Schmelzpunkt: 159-160°C.
• c) 1-(4-Chlorbenzoyl)-4-[4-(4,4-dimethyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und 2-Amino-2-methylpropanol.
  Schmelzpunkt: 145-146°C.
• d) 1-(4-Chlorbenzoyl)-4-[4-(2-thiazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und Cysteamin.
  Schmelzpunkt: 162-163°C.
• e) 1-(4-Chlorbenzoyl)-4-[4-(R-5-methyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und R-1-Amino-2-propanol.
  Schmelzpunkt: 104-106°C.
• f) 1-(4-Chlorbenzoyl)-4-[4-(S-5-methyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und S-1-Amino-2-propanol.
  Schmelzpunkt: 107-108°C.
• g) 1-(4-Chlorbenzoyl)-4-[3-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(3-methoxyimidoyl-benzyliden)piperidin-hydrochlorid und Ethanolamin.
  Schmelzpunkt: 90-92°C.
• h) 1-(4-Chlorbenzoyl)-4-[4-(5,5-dimethyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und 2-Hydroxy-2-methylpropylamin.
  Schmelzpunkt: 145-146°C.
• i) 1-(4-Chlorbenzolsulfonyl)-4-[4-(2-imidazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzolsulfonyl)-4-(4-methoxyimidoyl-benzyliden)piperidin-hydrochlorid und Ethylendiamin.
  Schmelzpunkt: 222-224°C.
• j) 1-(4-Chlorbenzolsulfonyl)-4-[4-(N-methyl-2-imidazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzolsulfonyl)-4-(4-methoxyimidoyl-benzyliden)piperidin-hydrochlorid und N-Methylethylendiamin. Farbloser Schaum.
  R_f-Wert: 0,24 (Aluminiumoxid; Essigsäureethylester).
• k) 1-(4-Chlorbenzoyl)-4-[4-(S-4-methyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und L-Alaninol.
  Schmelzpunkt: 143°C.
• l) 1-(4-Chlorbenzoyl)-4-[4-(R-4-methyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und D-Alaninol.
  Schmelzpunkt: 143°C.
• m) 1-(4-Chlorbenzoyl)-4-[4-(5-phenyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und 2-Amino-1-phenylethanol.
  Schmelzpunkt: 147°C.
• n) 1-(4-Chlorbenzoyl)-4-[4-(5-diethylaminomethyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und 1-Amino-3-diethylamino-2-propanol.
  Schmelzpunkt: 91°C.
• o) 1-(4-Chlorbenzoyl)-4-[4-(4-hydroxmethyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und DL-Serinol.
  Schmelzpunkt: 137°C.
• p) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)-α-methyl-benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-α-methyl-benzyliden)piperidin-hydrochlorid und Ethanolamin.
  Schmelzpunkt: 192°C.
• q) 1-(4-Chlorbenzoyl)-4-[4-(R-4-phenyl-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und R-2-Amino-2-phenylethanol.
  Schmelzpunkt: 130°C.
• r) 4-[4-(R-4-Benzyl-2-oxazolin-2-yl)benzyliden]-1-(4-chlorbenzoyl)piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und R-2-Amino-3-phenyl-1-propanol.
  Schmelzpunkt: 142°C.
• s) 4-[4-(S-4-Benzyl-2-oxazolin-2-yl)benzyliden]-1-(4-chlorbenzoyl)piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und S-2-Amino-3-phenyl-1-propanol.
  Schmelzpunkt: 142-143°C.
• t) 1-(4-Chlorbenzoyl)-4-[4-(4-((4-chlorbenzyl))-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und 4-Chlorphenylalaninol.
  Schmelzpunkt: 127°C.
• u) 1-(4-Chlorbenzoyl)-4-[4-(4-((2-methylthioethyl))-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und L-Methioninol.
  Schmelzpunkt: 95-96°C.
• v) 1-(4-Chlorbenzoyl)-4-[4-(4-((1-methyl-S-propyl))-2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyliden)piperidin und S-Isoleucinol.
  Schmelzpunkt: 101°C.
• w) 1-(4-Chlorbenzoyl)-4-[4-(2-imidazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und Ethylendiamin.
  Schmelzpunkt: 155-157°C.
• x) 1-(4-Chlorbenzoyl)-4-[4-(S-4-methyl-2-oxazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und L-Alaninol.
  Schmelzpunkt: 92-95°C.
• y) 1-(4-Chlorbenzoyl)-4-[4-(N-methyl-2-imidazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und N-Methylethylendiamin.
  Schmelzpunkt: 163-167°C.
• z) 1-(4-Chlorbenzoyl)-4-[4-(S-5-methyl-2-oxazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und S-1-Amino-2-propanol.
  Schmelzpunkt: 98-100°C.
• aa) 1-(4-Chlorbenzoyl)-4-[4-(R-5-methyl-2-oxazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und R-1-Amino-2-propanol.
  Schmelzpunkt: 99-101°C.
• ab) 1-(4-Chlorbenzoyl)-4-[4-(2-thiazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und Cysteamin.
  Schmelzpunkt: 106-108°C.
• ac) 1-(4-Chlorbenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-(4-ethoxyimidoyl-benzyl)piperidin-hydrochlorid und 3-Aminopropanol.
  Schmelzpunkt: 106-108°C.
• ad) 1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-3-(4-ethoxyimidoyl-benzyliden)piperidin-hydrochlorid und Ethanolamin.
  Schmelzpunkt: 151°C.

The following were obtained in the same way:

• a) 1- (4-Chlorobenzenesulfonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride and ethanolamine.
  Melting point: 191.5-192.5 ° C.
• b) 1- (4-Chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and 3-aminopropanol.
  Melting point: 159-160 ° C.
• c) 1- (4-Chlorobenzoyl) -4- [4- (4,4-dimethyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and 2-amino-2-methylpropanol.
  Melting point: 145-146 ° C.
• d) 1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and cysteamine.
  Melting point: 162-163 ° C.
• e) 1- (4-Chlorobenzoyl) -4- [4- (R-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and R-1-amino-2-propanol.
  Melting point: 104-106 ° C.
• f) 1- (4-Chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and S-1-amino-2-propanol.
  Melting point: 107-108 ° C.
• g) 1- (4-Chlorobenzoyl) -4- [3- (2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (3-methoxyimidoyl-benzylidene) piperidine hydrochloride and ethanolamine.
  Melting point: 90-92 ° C.
• h) 1- (4-Chlorobenzoyl) -4- [4- (5,5-dimethyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and 2-hydroxy-2-methylpropylamine.
  Melting point: 145-146 ° C.
• i) 1- (4-chlorobenzenesulfonyl) -4- [4- (2-imidazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride and ethylenediamine.
  Melting point: 222-224 ° C.
• j) 1- (4-Chlorobenzenesulfonyl) -4- [4- (N-methyl-2-imidazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride and N-methylethylenediamine. Colorless foam.
  R _f value: 0.24 (aluminum oxide; ethyl acetate).
• k) 1- (4-chlorobenzoyl) -4- [4- (S-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and L-alaninol.
  Melting point: 143 ° C.
• l) 1- (4-chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and D-alaninol.
  Melting point: 143 ° C.
• m) 1- (4-chlorobenzoyl) -4- [4- (5-phenyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and 2-amino-1-phenylethanol.
  Melting point: 147 ° C.
• n) 1- (4-chlorobenzoyl) -4- [4- (5-diethylaminomethyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and 1-amino-3-diethylamino-2-propanol.
  Melting point: 91 ° C.
• o) 1- (4-chlorobenzoyl) -4- [4- (4-hydroxymethyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and DL-Serinol.
  Melting point: 137 ° C.
• p) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) -α-methyl-benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-α-methyl-benzylidene) piperidine hydrochloride and ethanolamine.
  Melting point: 192 ° C.
• q) 1- (4-chlorobenzoyl) -4- [4- (R-4-phenyl-2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and R-2-amino-2-phenylethanol.
  Melting point: 130 ° C.
• r) 4- [4- (R-4-Benzyl-2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and R-2-amino-3-phenyl-1-propanol.
  Melting point: 142 ° C.
• s) 4- [4- (S-4-Benzyl-2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and S-2-amino-3-phenyl-1-propanol.
  Melting point: 142-143 ° C.
• t) 1- (4-Chlorobenzoyl) -4- [4- (4 - ((4-chlorobenzyl)) - 2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and 4-chlorophenylalaninol.
  Melting point: 127 ° C.
• u) 1- (4-Chlorobenzoyl) -4- [4- (4 - ((2-methylthioethyl)) - 2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and L-methioninol.
  Melting point: 95-96 ° C.
• v) 1- (4-Chlorobenzoyl) -4- [4- (4 - ((1-methyl-S-propyl)) - 2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and S-isoleucinol.
  Melting point: 101 ° C.
• w) 1- (4-chlorobenzoyl) -4- [4- (2-imidazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and ethylenediamine.
  Melting point: 155-157 ° C.
• x) 1- (4-chlorobenzoyl) -4- [4- (S-4-methyl-2-oxazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and L-alaninol.
  Melting point: 92-95 ° C.
• y) 1- (4-chlorobenzoyl) -4- [4- (N-methyl-2-imidazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and N-methylethylenediamine.
  Melting point: 163-167 ° C.
• z) 1- (4-Chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and S-1-amino-2-propanol.
  Melting point: 98-100 ° C.
• aa) 1- (4-Chlorobenzoyl) -4- [4- (R-5-methyl-2-oxazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and R-1-amino-2-propanol.
  Melting point: 99-101 ° C.
• ab) 1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and cysteamine.
  Melting point: 106-108 ° C.
• ac) 1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and 3-aminopropanol.
  Melting point: 106-108 ° C.
• ad) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -3- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride and ethanolamine.
  Melting point: 151 ° C.

Example 2 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidi n

To 6 g (0.02 mol) of diethyl 4- (2-oxazolin-2-yl) benzylphosphonate in 80 ml of tetrahydrofuran, 12.5 ml (0.021 mol) of a 1.6 M solution of n-butyllithium are added at -50 ° C Dropped n-hexane. The deep red solution is stirred for 25 minutes at -55 ° C. and then 4.7 g (0.02 mol) of N- (4-chlorobenzoyl) -4-piperidone in 20 ml of tetrahydrofuran are added dropwise. After 5 hours of stirring at room temperature, the reaction mixture is stirred into 300 ml of water, the precipitate is filtered off with suction after a further 20 minutes and recrystallized from ethanol. 3.2 g (42% of theory) of the title compound identical to the product mentioned in Example 1 are obtained.

• a) 1-(4-Methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-(4-Methylbenzoyl)-4-piperidon.
  Schmelzpunkt: 169-171°C.
• b) 1-(Dihydrocinnamoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-Dihydrocinnamoyl-4-piperidon.
  Schmelzpunkt: 98-100°C.
• c) 1-(4-Chlorcinnamoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-(4-Chlorcinnamoyl)-4-piperidon.
  R_f-Wert: 0,86 (Aluminiumoxid; Essigsäureethylester)
• d) 1-Hexanoyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-Hexanoyl-4-piperidon.
  Schmelzpunkt: 98-100°C.
• e) 4-[4-(2-Oxazolin-2-yl)benzyliden-1-pivaloylpiperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-Pivaloyl-4-piperidon.
  Schmelzpunkt: 163-165°C.
• f) 1-Cyclohexancarbonyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-(2-Oxazolin-2-yl)benzylphosphonsäurediethylester und N-Cyclohexancarbonyl-4-piperidon.
  Schmelzpunkt: 163-164°C.

The following were obtained in the same way:

• a) 1- (4-Methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N- (4-methylbenzoyl) -4-piperidone.
  Melting point: 169-171 ° C.
• b) 1- (Dihydrocinnamoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-dihydrocinnamoyl-4-piperidone.
  Melting point: 98-100 ° C.
• c) 1- (4-Chlorocinnamoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N- (4-chlorocinnamoyl) -4-piperidone.
  R _f value: 0.86 (aluminum oxide; ethyl acetate)
• d) 1-Hexanoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-hexanoyl-4-piperidone.
  Melting point: 98-100 ° C.
• e) 4- [4- (2-Oxazolin-2-yl) benzylidene-1-pivaloylpiperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-pivaloyl-4-piperidone.
  Melting point: 163-165 ° C.
• f) 1-Cyclohexane carbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-cyclohexanecarbonyl-4-piperidone.
  Melting point: 163-164 ° C.

Example 3 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine

120 mg (0.5 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 75 mg (0.75 mmol) of triethylamine in 3 ml of ethyl acetate and 2 ml of methylene chloride are reduced to -5 to -10 Cooled ° C and 104.3 mg (0.5 mmol) of 4-trifluoromethylbenzoyl chloride were added. The mixture is stirred for 1.5 hours at room temperature, diluted with ethyl acetate, washed successively with water, 2N sodium hydroxide solution and saturated sodium chloride solution, dried and evaporated. 115 mg (56% of theory) of the title compound of melting point 142 ° C. are obtained.
1 H NMR Spectrum (200 MHz, CDCl₃); Signals at ppm:
2.3-2.7 (m, 4H), 3.3-3.5 (m, 2H), 3.7-3.9 (m, 2H), 4.05 (t, 3H), 4.4 (t, 3H), 6.4 (s, 1H), 7.2 ( d, 2H), 7.55 (d, 2H), 7.7 (d, 2H), 7.9 (d, 2H).

• a) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-stearoylpiperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und Stearinsäurechlorid.
  Schmelzpunkt: 72°C.
• b) 1-Cyclopropylcarbonyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und Cyclopropancarbonsäurechlorid.
  Schmelzpunkt: 117°C.
• c) 1-(4-Chlor-3-methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Chlor-3-methylbenzoylchlorid.
  Schmelzpunkt: 145°C.
• d) 1-(3,4-Dichlorphenylacetyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3,4-Dichlorphenylessigsäurechlorid.
  Schmelzpunkt: 132°C.
• e) 1-(4-Fluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Fluorbenzoesäurechlorid.
  Schmelzpunkt: 146°C.
• f) 1-(5-Chlor-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 5-Chlorthiophencarbonsäurechlorid.
  Schmelzpunkt: 145°C.
• g) 1-(2-Naphthylacetyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 2-Naphthalinessigsäurechlorid.
  Schmelzpunkt: 133°C.
• h) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]hexahydroazepin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]hexahydroazepin und 4-Chlorbenzoylchlorid.
  Zähes Öl.
  R_f-Wert: 0,42 (Aluminiumoxid; Petrolether/Essigsäureethylester = 1:1, v:v).
• i) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Chlorbenzoylchlorid.
  Schmelzpunkt: 140°C.
• j) 1-(1-Naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 1-Naphthalincarbonsäurechlorid.
  Schmelzpunkt: 146-149°C.
• k) 1-(3,4-Difluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3,4-Difluorbenzoylchlorid.
  Schmelzpunkt: 133-135°C.
• l) 1-(3,5-Bis-trifluormethylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3,5-Bis-trifluormethylbenzoylchlorid.
  Schmelzpunkt: 137°C.
• m) 1-(4-Cyanobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Cyanobenzoylchlorid.
  Schmelzpunkt: 166°C.
• n) 1-(2-Naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 2-Naphthalincarbonsäurechlorid.
  Schmelzpunkt: 167°C.
• o) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(2-trifluormethylbenzoyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 2-Trifluormethylbenzoylchlorid.
  Schmelzpunkt: 128°C.
• p) 1-(3,4-Dichlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3,4-Dichlorbenzoylchlorid.
  Schmelzpunkt: 159°C.
• q) 1-(4-Fluor-1-naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Fluornapthalincarbonsäurechlorid.
  Schmelzpunkt: zuerst bei 132°C, dann nach zwischenzeitlichen Erstarren bei 157°C.
• r) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(pentafluorbenzoyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und Pentafluorbenzoylchlorid.
  Schmelzpunkt: 212°C.
• s) 1-Benzoyl-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und Benzoylchlorid.
  Schmelzpunkt: 136°C.
• t) 1-(4-Methylsulfonylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Methylsulfonylbenzoylchlorid.
  Schmelzpunkt: 191°C.
• u) 1-(4-tert.-Butylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-tert.-Butylbenzoylchlorid.
  Schmelzpunkt: 193°C.
• v) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(3-trifluormethylbenzoyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3-Trifluormethylbenzoylchlorid.
  Schmelzpunkt: 99°C.
• w) 1-(3-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 3-Chlorbenzoylchlorid.
  Schmelzpunkt: 116°C.
• x) 1-(4-Methoxybenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Methoxybenzoylchlorid.
  Schmelzpunkt: 153°C.
• y) 1-(2,5-Difluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 2,5-Difluorbenzoylchlorid.
  Schmelzpunkt: 137°C.
• z) 1-(4-Brombenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Brombenzoylchlorid.
  Schmelzpunkt: 199°C.
• aa) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(1,2,3,4-Tetrahydro-2-naphthylcarbonyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 1,2,3,4-Tetrahydro-2-naphthalincarbonsäurechlorid.
  Schmelzpunkt: 151°C.
• ab) 1-(4-Nitrobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Nitrobenzoylchlorid.
  Schmelzpunkt: 192°C.
• ac) 1-(4-Chlorphenylacetyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin und 4-Chlorphenylacetylchlorid.
  Schmelzpunkt: 107°C.
• ad) 1-Benzoyl-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und Benzoylchlorid.
  Schmelzpunkt: 78-80°C.
• ae) 1-(2-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 2-Chlorbenzoylchlorid.
  Schmelzpunkt: 105-108°C.
• af) 1-(3-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 3-Chlorbenzoylchlorid.
  Harz.
  R_f-Wert: 0,6 (Kieselgel; Essigsäureethylester/Petrolether = 10:2, v:v).
• ag) 1-(4-Fluorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Fluorbenzoylchlorid.
  Schmelzpunkt: 111-113°C.
• ah) 1-(4-tert.-Butylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-tert.-Butylbenzoylchlorid.
  Harz.
  R_f-Wert: 0,3 (Kieselgel; Essigsäureethylester).
• ai) 1-(4-Biphenylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Biphenylcarbonylchlorid.
  Schmelzpunkt: 158-160°C.
• aj) 1-(2-Naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 2-Naphthalincarbonsäurechlorid.
  Schmelzpunkt: 100-105°C.
• ak) 1-(1-Naphthylcarbonyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 1-Naphthalincarbonsäurechlorid.
  Schmelzpunkt: 70-73°C.
• al) 1-(4-Chlorphenylsulfonyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Chlorphenylsulfonylchlorid.
  Schmelzpunkt: 155-157°C.
• am) 1-(4-Methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Methylbenzoylchlorid.
  Schmelzpunkt: 143-145°C.
• an) 4-(4-Cyanobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und 4-Cyanobenzoylchlorid.
  Schmelzpunkt: 148-150°C.
• ao) 4-[4-(2-Oxazolin-2-yl)benzyl]-1-(4-pyridoyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyl]piperidin und Isonicotinsäurechlorid.
  Schmelzpunkt: 148-150°C.
• ap) 1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl)benzyliden]pyrrolidin
  aus 3-[4-(2-Oxazolin-2-yl)benzyliden]pyrrolidin und 4-Chlorbenzoylchlorid.
  R_f-Wert: 0,36 (Kieselgel; Methylenchlorid/Methanol = 24:1, v:v).

The following were obtained in the same way:

• a) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1-stearoylpiperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and stearic acid chloride.
  Melting point: 72 ° C.
• b) 1-Cyclopropylcarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and cyclopropanecarboxylic acid chloride.
  Melting point: 117 ° C.
• c) 1- (4-Chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-chloro-3-methylbenzoyl chloride.
  Melting point: 145 ° C.
• d) 1- (3,4-dichlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3,4-dichlorophenylacetic acid chloride.
  Melting point: 132 ° C.
• e) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-fluorobenzoic acid chloride.
  Melting point: 146 ° C.
• f) 1- (5-Chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 5-chlorothiophenecarboxylic acid chloride.
  Melting point: 145 ° C.
• g) 1- (2-Naphthylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2-naphthalene acetic acid chloride.
  Melting point: 133 ° C.
• h) 1- (4-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] hexahydroazepine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] hexahydroazepine and 4-chlorobenzoyl chloride.
  Viscous oil.
  R _f value: 0.42 (aluminum oxide; petroleum ether / ethyl acetate = 1: 1, v: v).
• i) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-chlorobenzoyl chloride.
  Melting point: 140 ° C.
• j) 1- (1-Naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 1-naphthalenecarboxylic acid chloride.
  Melting point: 146-149 ° C.
• k) 1- (3,4-difluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3,4-difluorobenzoyl chloride.
  Melting point: 133-135 ° C.
• l) 1- (3,5-bis-trifluoromethylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3,5-bis-trifluoromethylbenzoyl chloride.
  Melting point: 137 ° C.
• m) 1- (4-Cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-cyanobenzoyl chloride.
  Melting point: 166 ° C.
• n) 1- (2-Naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2-naphthalenecarboxylic acid chloride.
  Melting point: 167 ° C.
• o) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (2-trifluoromethylbenzoyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2-trifluoromethylbenzoyl chloride.
  Melting point: 128 ° C.
• p) 1- (3,4-dichlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3,4-dichlorobenzoyl chloride.
  Melting point: 159 ° C.
• q) 1- (4-fluoro-1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-fluoronapthalene carboxylic acid chloride.
  Melting point: first at 132 ° C, then after intermediate solidification at 157 ° C.
• r) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (pentafluorobenzoyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and pentafluorobenzoyl chloride.
  Melting point: 212 ° C.
• s) 1-Benzoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and benzoyl chloride.
  Melting point: 136 ° C.
• t) 1- (4-Methylsulfonylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-methylsulfonylbenzoyl chloride.
  Melting point: 191 ° C.
• u) 1- (4-tert-Butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-tert-butylbenzoyl chloride.
  Melting point: 193 ° C.
• v) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (3-trifluoromethylbenzoyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3-trifluoromethylbenzoyl chloride.
  Melting point: 99 ° C.
• w) 1- (3-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3-chlorobenzoyl chloride.
  Melting point: 116 ° C.
• x) 1- (4-methoxybenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-methoxybenzoyl chloride.
  Melting point: 153 ° C.
• y) 1- (2,5-difluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2,5-difluorobenzoyl chloride.
  Melting point: 137 ° C.
• z) 1- (4-bromobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-bromobenzoyl chloride.
  Melting point: 199 ° C.
• aa) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (1,2,3,4-tetrahydro-2-naphthylcarbonyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid chloride.
  Melting point: 151 ° C.
• ab) 1- (4-nitrobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-nitrobenzoyl chloride.
  Melting point: 192 ° C.
• ac) 1- (4-chlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-chlorophenylacetyl chloride.
  Melting point: 107 ° C.
• ad) 1-benzoyl-4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and benzoyl chloride.
  Melting point: 78-80 ° C.
• ae) 1- (2-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 2-chlorobenzoyl chloride.
  Melting point: 105-108 ° C.
• af) 1- (3-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 3-chlorobenzoyl chloride.
  Resin.
  R _f value: 0.6 (silica gel; ethyl acetate / petroleum ether = 10: 2, v: v).
• ag) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-fluorobenzoyl chloride.
  Melting point: 111-113 ° C.
• ah) 1- (4-tert-butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-tert-butylbenzoyl chloride.
  Resin.
  R _f value: 0.3 (silica gel; ethyl acetate).
• ai) 1- (4-Biphenylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-biphenylcarbonyl chloride.
  Melting point: 158-160 ° C.
• aj) 1- (2-Naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 2-naphthalenecarboxylic acid chloride.
  Melting point: 100-105 ° C.
• ak) 1- (1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 1-naphthalenecarboxylic acid chloride.
  Melting point: 70-73 ° C.
• al) 1- (4-chlorophenylsulfonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-chlorophenylsulfonyl chloride.
  Melting point: 155-157 ° C.
• am) 1- (4-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-methylbenzoyl chloride.
  Melting point: 143-145 ° C.
• an) 4- (4-cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-cyanobenzoyl chloride.
  Melting point: 148-150 ° C.
• ao) 4- [4- (2-Oxazolin-2-yl) benzyl] -1- (4-pyridoyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and isonicotinic acid chloride.
  Melting point: 148-150 ° C.
• ap) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine
  from 3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine and 4-chlorobenzoyl chloride.
  R _f value: 0.36 (silica gel; methylene chloride / methanol = 24: 1, v: v).

Example 4 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-pentinoyl) piperidine

356 mg (2.2 mmol) of N, N'-carbonyldiimidazole in 3 ml of tetrahydrofuran are mixed with 200 mg (2 mmol) of 4-pentynic acid in 2 ml of tetrahydrofuran at room temperature. The mixture is stirred at 40 ° C for one hour. 363 mg (1.5 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine are then added and the mixture is stirred at 40 ° C. for a further 2 hours. The reaction solution is then concentrated and the residue is purified by column chromatography (silica gel; ethyl acetate). 320 mg (66% of theory) of the title compound of melting point 118 ° C. are obtained.
1 H NMR Spectrum (200 MHz, CDCl₃); Signals at ppm:
2.0 (s, 1H), 2.3-2.7 (m, 8H), 3.4-3.8 (m, 4H), 4.05 (t, 2H), 4.4 (t, 2H), 6.4 (s, 1H), 7.2 ( d, 2H), 2.9 (d, 2H).

• a) 4-[4-(2-Oxazolin-2-yl)benzyliden]-1-(4-phenyl-3-butenoyl)piperidin
  aus 4-[4-(2-Oxazolin-2-yl)benzyliden]piperidin, 4-Phenyl-3-butensäure und N,N'-carbonyldiimidazol.
  Schmelzpunkt: 139°C.

In the same way was obtained:

• a) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-phenyl-3-butenoyl) piperidine
  from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine, 4-phenyl-3-butenoic acid and N, N'-carbonyldiimidazole.
  Melting point: 139 ° C.

Example 5 4- [4- (2-Oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine

441 mg (1 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine are dissolved in 10 ml of anhydrous ethanol and 2.5 ml of ethyl acetate in the presence of 0.5 g Palladium-carbon (10%) hydrogenated (room temperature, 30 minutes, hydrogen pressure 50 psi). The catalyst is then filtered off with suction, the filtrate is evaporated at a bath temperature of 50 ° C. under reduced pressure and the residue is purified by column chromatography (silica gel; ethyl acetate). 200 mg (48% of theory) of the title compound of melting point 115 ° C. are obtained.
1 H NMR Spectrum (200 MHz, CDCl₃); Signals at ppm:
1.0-1.4 (m, 2H), 1.6-1.9 (m, 3H), 2.6 (d, 2H), 2.7-3.1 (m, 2H), 3, 6 (m, 1H), 4.05 (t, 2H), 4.4 (t, 2H), 4.7 (m, 1H), 7.15 (d, 2H), 7.5 (d, 2H) ), 7.65 (d, 2H), 7.85 (d, 2H).

• a) 1-(4-Chlorbenzoyl)-4-[4-(R-4-methyl-2-oxazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-[4-(R-4-methyl-2-oxazolin-2-yl)benzyliden]piperidin
  Farbloses Harz.
  R_f-Wert: 0,37 (Kieselgel; Essigsäureethylester)
• b) 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-4-[4-(2-oxazolin-2-yl)benzyliden]piperidin.
  Schmelzpunkt: 136-138°C.
• c) 1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl))benzyl]piperidin
  aus 1-(4-Chlorbenzoyl)-3-[4-(2-oxazolin-2-yl)benzyliden]piperidin.
  Farbloses Harz.
  R_f-Wert: 0,5 (Kieselgel; Essigsäureethylester)

The following were obtained in the same way:

• a) 1- (4-Chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine
  Colorless resin.
  R _f value: 0.37 (silica gel; ethyl acetate)
• b) 1- (4-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine.
  Melting point: 136-138 ° C.
• c) 1- (4-Chlorobenzoyl) -3- [4- (2-oxazolin-2-yl)) benzyl] piperidine
  from 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] piperidine.
  Colorless resin.
  R _f value: 0.5 (silica gel; ethyl acetate)

Example 6 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine

0.4 g (0.95 mmol) of 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-hydroxyethylaminocarbonyl) benzylidene] piperidine in 20 ml of tetrahydrofuran are added in portions at the boiling point for 45 minutes at 0, 3 g (1.1 mmol) of methyl N- (triethylamoniosulfonyl) carbamate (Burgess reagent) were added. It is further heated for two hours, evaporated and the residue is mixed with water, extracted three times with methylene chloride, dried with anhydrous sodium sulfate, evaporated and the residue is purified on a silica gel column (ethyl acetate / petroleum ether = 10: 4, v: v). 0.105 g (26% of theory) of the title compound of melting point 158-160 ° C. is obtained.
1 H NMR Spectrum (200 MHz, DMSO-d₆); Signals at ppm:
2.4 (m, 4H), 3.4-3.7 (m, 4H), 3.95 (t, 2H), 4.4 (t, 2H), 6.35 (s, 1H), 7.3-7.7 (m, 7H).

• a) 1-(4-Chlorbenzoyl)-4-[3-methyl-4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-[4-(2-hydroxyethylaminocarbonyl)-3-methyl-benzyliden]piperidin und Burgess-Reagenz.
  Schmelzpunkt: 88-90°C.
• b) 4-[2-Brom-4-(2-oxazolin-2-yl)benzyliden]-1-(4-chlorbenzoyl)piperidin
  aus 4-[2-Brom-4-(2-hydroxyethylaminocarbonyl)benzyliden]-1-(4-chlorbenzoyl)piperidin und Burgess-Reagenz.
  Schmelzpunkt: 185-187°C.
• c) 1-[4-Chlorbenzoyl)-4-[2-methoxy-4-(2-oxazolin-2-yl)benzyliden]piperidin
  aus 1-(4-Chlorbenzoyl)-4-[4-(2-hydroxyethylaminocarbonyl)-2-methoxy-benzyliden]piperidin und Burgess-Reagenz.
  Schmelzpunkt: 150-152°C.

It was represented in the same way:

• a) 1- (4-Chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -3-methyl-benzylidene] piperidine and Burgess reagent.
  Melting point: 88-90 ° C.
• b) 4- [2-bromo-4- (2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine
  from 4- [2-bromo-4- (2-hydroxyethylaminocarbonyl) benzylidene] -1- (4-chlorobenzoyl) piperidine and Burgess reagent.
  Melting point: 185-187 ° C.
• c) 1- [4-chlorobenzoyl) -4- [2-methoxy-4- (2-oxazolin-2-yl) benzylidene] piperidine
  from 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -2-methoxy-benzylidene] piperidine and Burgess reagent.
  Melting point: 150-152 ° C.

The production of pharmaceutical forms of application is described below using a few examples:

Example I Tablets containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine Composition:

1 tablet contains: Active ingredient 5.0 mg Milk sugar 148.0 mg Potato starch 65.0 mg Magnesium stearate 2.0 mg 220.0 mg

Production method:

A 10% slime is made from potato starch by heating. The active substance, milk sugar and the remaining potato starch are mixed and granulated with the above mucus through a sieve with a mesh size of 1.5 mm. The granules are dried at 45 ° C., rubbed again through the above sieve, mixed with magnesium stearate and pressed into tablets. Tablet weight: 220 mg Stamp: 9 mm

Example II Dragèes with 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

The tablets produced according to Example I are covered by a known method with an envelope which is essentially consists of sugar and talc. The finished dragèes are polished with the help of beeswax. Dragée weight: 300 mg

Example III Suppositories with 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine Composition:

1 suppository contains: Active ingredient 5.0 mg Suppository mass (e.g. Witepsol W 45 ^(R) ) 1,695.0 mg 1,700.0 mg

Production method:

The finely powdered active substance is suspended in the molten suppository mass, which has been cooled to 40 ° C. The mass is poured into slightly pre-cooled suppository molds at 37 ° C. Suppository weight: 1.7 g.

Example IV Capsules with 5 mg of N- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine Composition:

1 capsule contains: Active substance 5.0 mg Lactose 82.0 mg Strength 82.0 mg Magnesium stearate 1.0 mg 170.0 mg

Production method:

The powder mixture is mixed intensively and filled into size 3 hard gelatin capsules on a capsule filling machine, the final weight being continuously checked.

Example V Tablets containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine Composition:

1 tablet contains: Active ingredient 5.0 mg Milk sugar 148.0 mg Potato starch 65.0 mg Magnesium stearate 2.0 mg 220.0 mg

Production method:

A 10% slime is made from potato starch by heating. The active substance, milk sugar and the remaining potato starch are mixed and granulated with the above mucus through a sieve with a mesh size of 1.5 mm. The granules are dried at 45 ° C., rubbed again through the above sieve, mixed with magnesium stearate and pressed into tablets. Tablet weight: 220 mg Stamp: 9 mg

Example VI Cream for topical administration with 1 g of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

A formulation for the topical administration of the compounds of the formula I can have the following composition 1. Active ingredient 1.0 g 2nd Stearyl alcohol 4.0 g 3rd Cetyl alcohol 4.0 g 4th mineral oil 3.0 g 5. Polysorbate 60 4.5 g 6. Sorbitan stearate 4.5 g 7. Propylene glycol 10.0 g 8th. Methyl paraben 0.18 g 9. Propyl paraben 0.02 g 10th water qs ad 100.00 g

The components 2-6 are heated to 80 ° C until everything has melted. Then component 1 is dissolved in the oily phase. Constituents 7 and 10 are heated to 90 ° C. and constituents 8 and 9 are dissolved in the aqueous phase thus obtained. Thereafter, the aqueous phase is added to the oil phase and stirred rapidly so that an emulsion is obtained. Then allowed to cool slowly to 50 ° C to solidify the emulsion. With further stirring, the preparation is cooled to room temperature.

The following example describes the production of a feed for laying hens:

Example VII Feed for laying hens, containing 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidi n as active ingredient

Corn 633 g / kg Soybean meal 260 g / kg Meat meal 40 g / kg Feed fat 25 g / kg Soybean oil 17 g / kg Bicalcium phosphate 12 g / kg Calcium carbonate 6 g / kg Vitamin-mineral mixture 5 g / kg Active ingredient 2 g / kg

After thorough mixing, these components in the stated amounts result in 1 kg of feed.

Claims (11)

1. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of general formula I

   

   (wherein:
   n denotes the numbers 0 or 1;
   m denotes the numbers 1 or 2;
   p denotes the numbers 0 or 1;
   A denotes a single bond, a straight-chained or branched C₁₋₁₇-alkylene group, a C₂₋₁₇-alkenylene group or a C₂₋₄-alkynylene group;
   W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,
   X denotes a carbonyl or sulphonyl group;
   Y denotes an oxygen or sulphur atom or an 〉NR¹¹ group;
   R¹ to R⁶ in each case denote a hydrogen atom, or
   one, two or three of the groups R¹ to R⁶, which groups may be identical or different, denote a straight-chained or branched C₁₋₄-alkyl group which may be substituted by a hydroxy, alkoxy, alkylthio or dialkylamino group or by a phenyl group which is optionally substituted by a halogen atom or an alkyl group, or denote an alkoxycarbonyl group and the remaining groups R¹ to R⁶ each denote a hydrogen atom;
   whilst one, two or all three of the groups R¹, R³ and R⁵ may also denote a phenyl group which is optionally substituted by an alkyl group or by a halogen atom;
   R⁷ denotes a hydrogen or halogen atom or an alkyl or alkoxy group;
   R⁸ and R⁹ independently of each other denote a hydrogen atom, or an alkyl group;
   R¹⁰ denotes a hydrogen atom, a C₃₋₆-cycloalkyl group, a phenyl group optionally substituted by a halogen atom, by a straight-chained or branched C₁₋₄-alkyl group, a trifluoromethyl, alkoxy, cyano, nitro, alkylsulphonyl or phenyl group, a phenyl group substituted by two trifluoromethyl groups, two to five halogen atoms or by one halogen atom and an alkyl group, a naphthyl or tetrahydronaphthyl group optionally substituted by a fluorine atom, a pyridyl group or a thienyl group optionally substituted by a halogen atom or by an alkyl group; and
   R¹¹ denotes a hydrogen atom or an alkyl group;
   whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and
   wherein, unless otherwise stated, the above mentioned alkyl, alkoxy, alkylthio and alkylsulphonyl groups may each contain 1 to 3 carbon atoms and the above mentioned halogen atoms may each denote a fluorine, chlorine or bromine atom)
   and the enantiomers, diastereomers and salts thereof.
2. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula Ia according to claim 1,

   

   (wherein:
   n denotes the numbers 0 or 1;
   m denotes the numbers 1 or 2;
   p denotes the number 0 or 1;
   A denotes a single bond, a straight-chained or branched C₁₋₁₇-alkylene group, or a C₂₋₄-alkenylene or a C₂₋₄-alkynylene group;
   W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,
   X denotes a carbonyl or sulphonyl group;
   Y denotes an oxygen or sulphur atom or an 〉NR¹¹ group;
   R¹ to R⁴ in each case denote a hydrogen atom, or
   one or two of the groups R¹ to R⁴, which may be identical or different, each denote a straight-chained or branched C₁₋₄-alkyl group which may be substituted by a hydroxy, alkylthio or dialkylamino group or by a phenyl group itself optionally substituted by a halogen atom, or denote a phenyl group, and the remaining groups R¹ to R⁴ each denote a hydrogen atom;
   R⁵ and R⁶, which may be identical or different, denote a hydrogen atom or a methyl group;
   R⁷ denotes a hydrogen or halogen atom or an alkyl or alkoxy group,
   R⁸ denotes a hydrogen atom, or an alkyl group;
   R⁹ denotes a hydrogen atom;
   R¹⁰ denotes a hydrogen atom, a C₃₋₆-cycloalkyl group, a phenyl group optionally substituted by one or two halogen atoms, a straight-chained or branched C₁₋₄-alkyl group, a trifluoromethyl, methoxy, cyano, nitro, methylsulphonyl or phenyl group; a phenyl group substituted by two trifluoromethyl groups or by a halogen atom and a methyl group; a phenyl group substituted by three to five fluorine atoms; a naphthyl group optionally substituted by a fluorine atom; a tetrahydronaphthyl or pyridyl group or a thienyl group optionally substituted by a halogen atom; and
   R¹¹ denotes a hydrogen atom or an alkyl group;
   whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and
   wherein, unless otherwise stated, the above mentioned alkyl groups may each contain 1 to 3 carbon atoms and the above mentioned halogen atoms may each denote a fluorine, chlorine or bromine atom)
   and the enantiomers, diastereomers and salts thereof.
3. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula Ia, according to claim 2,
   wherein:
   n denotes the numbers 0 or 1,
   m denotes the numbers 1 or 2,
   p denotes the number 0 or 1,
   A denotes a single bond, a C₁₋₁₇-straight-chained or branched alkylene or C₂₋₄-alkenylene group,
   W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,
   X denotes a carbonyl or sulphonyl group,
   Y denotes an oxygen atom or an 〉NR¹¹ group,
   R¹ to R⁴ in each case denote a hydrogen atom or
   one or two of the groups R¹ to R⁴ denote a straight-chained or branched C₁₋₄-alkyl group, and the remaining groups R¹ to R⁴ each denote a hydrogen atom,
   R⁵ and R⁶, which may be identical or different, denote a hydrogen atom or a methyl group,
   R⁷ denotes a hydrogen or halogen atom, or a methyl or methoxy group,
   R⁸ denotes a hydrogen atom or a methyl group,
   R⁹ denotes a hydrogen atom,
   R¹⁰ denotes a hydrogen atom, a C₃₋₆-cycloalkyl group, a phenyl group optionally substituted by one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl groups or by a halogen atom and an alkyl group, a 1-naphthyl group optionally substituted by a fluorine atom in the 4-position, a 2-naphthyl group, a 1,2,3,4-tetrahydro-2-naphthyl group, a pyridyl or 4-biphenyl group, or a thienyl group optionally substituted by a halogen atom,
   R¹¹ denotes a hydrogen atom or a methyl group,
   whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and
   wherein, unless otherwise stated, the above mentioned alkyl moieties may each contain 1 to 3 carbon atoms and the above mentioned halogen atoms may each denote a fluorine or chlorine atom,
   and the enantiomers, diastereomers and salts thereof.
4. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula Ia, according to claim 2,
   wherein:
   n denotes the numbers 0 or 1,
   m denotes the number 1,
   p denotes the number 0 or 1,
   A denotes a single bond,
   W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,
   X denotes a carbonyl group,
   Y denotes an oxygen atom,
   R¹ to R⁶ in each case denote a hydrogen atom,
   R⁷ denotes a hydrogen or halogen atom or a methyl group,
   R⁸ and R⁹ each denote a hydrogen atom,
   R¹⁰ denotes a phenyl group substituted in the 4-position by a fluorine, chlorine or bromine atom or by a trifluoromethyl group, or R¹⁰ denotes a 4-chloro-3-methylphenyl group, a 5-chloro-2-thienyl group or a cyclohexyl group,
   and the salts thereof.
5. The following compounds of the general formula I according to claim 1:

   (1) 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

   (2) 1-(4-chlorobenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzylidene]piperidine (3) 4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-trifluoro

   methylbenzoyl)piperidine

   (4) 1-(4-chloro-3-methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

   (5) 1-(4-fluorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

   (6) 1-(5-chloro-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

   (7) 1-cyclohexanecarbonyl-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

   (8) 4-[4-(2-oxazolin-2-yl)benzyl]-1-(4-trifluoromethylbenzoyl)piperidine

   (9) 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)-benzyl]piperidine

   (10) 1-(4-chlorobenzoyl)-3-[4-(2-oxazolin-2-yl)benzylidene]pyrrolidine

   (11) 1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-oxazolin-2-yl)benzylidene]piperidine

   (12) 1-(4-chlorobenzoyl)-4-[3-methyl-4-(2-oxazolin-2-yl)benzylidene]piperidine

   and the salts thereof.
6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids.
7. Medicaments, containing a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 optionally together with one or more inert excipients and/or diluents.
8. Use of a compound according to at least one of claims 1 to 6 for the preparation of a drug for inhibiting cholesterol biosynthesis, for the treatment or prophylaxis of hyperlipidaemias, for the treatment of disorders which are connected with excessive cell proliferation, for the prophylaxis and treatment of gallstone trouble or for treating mycoses.
9. Use of a compound according to at least one of claims 1 to 6 for the preparation of a foodstuff for laying hens for the production of low-cholesterol eggs.
10. Process for the preparation of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated into one or more inert excipients and/or diluents by non-chemical means.
11. Process for the preparation of the compounds according to at least one of claims 1 to 6, characterized in that

    a) a compound of the general formula II

    

    (wherein
    m, p, A, W¹, W², X and R⁷ to R¹⁰ are as defined in claims 1 to 5 and R¹² denotes a C₁₋₁₀-alkyl group)
    is reacted with a compound of the general formula III

    

    wherein
    n, Y and R¹ to R⁶ are as defined in claims 1 to 5, or

    b) in order to prepare compounds of general formula I wherein n, m, p, A, X, Y and R¹ to R¹⁰ are defined as in claims 1 to 5 and W¹ and W² together denote a carbon-carbon bond, a phosphonate ester of the general formula IV

    

    (wherein
    n, Y and R¹ to R⁸ are as defined in claims 1 to 5 and R¹³ denotes a C₁₋₁₀-alkyl group)
    is reacted with a compound of the general formula V,

    

    wherein
    m, p, A, X, R⁹ and R¹⁰ are as defined in claims 1 to 5, or

    c) a compound of the general formula VI

    

    (wherein
    n, m, p, W¹, W², Y and R¹ to R⁹ are as defined in Claims 1 to 5)
    is reacted with a compound of the general formula VII
    
    
    
            Z¹ - X - A - R¹⁰   (VII)
    
    
    
    wherein
    A, X and R¹⁰ are as defined in claims 1 to 5 and Z¹ denotes a reactive leaving group, or

    d) in order to prepare compounds of general formula I wherein n, m, p, X and R⁷ to R⁹ have the meanings given in claims 1 to 5, A denotes a single bond or a straight-chained or branched C₁₋₁₇-alkylene group, W¹ and W² each denote a hydrogen atom and Y denotes an oxygen atom or the 〉NR¹¹ group, where R¹¹ is defined as in claims 1 to 5, R¹ to R⁶ have the meanings given in claims 1 to 5 with the exception of the straight-chained or branched C₁₋₄-alkyl group substituted by an alkylthio group, and R¹⁰ has the meanings given in claims 1 to 5 with the exception of the thienyl group optionally substituted by a halogen atom, whilst A cannot be a single bond if X denotes a sulphonyl group and R¹⁰ denotes a hydrogen atom,
    a compound of general formula I'

    

    wherein wherein
    n, m, p, X and R⁷ to R⁹ have the meanings given in claims 1 to 5, A' denotes a single bond or a straight-chained or branched C₁₋₁₇-alkylene group, W¹' and W²' together denote a carbon-carbon bond and Y' denotes an oxygen atom or the 〉NR¹¹ group, where R¹¹ is defined as in claims 1 to 5, R¹ to R⁶ have the meanings given in claims 1 to 5 with the exception of the straight-chained or branched C₁₋₄-alkyl group substituted by an alkylthio group, and R¹⁰ has the meanings given in claims 1 to 5 with the exception of the thienyl group optionally substituted by a halogen atom, whilst A cannot denote a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, is hydrogenated or

    e) in order to prepare compounds of general formula I wherein n, m, p, A, X, W¹, W² and R¹ to R¹⁰ have the meanings given in claims 1 to 5 and Y denotes an oxygen atom, a compound of general formula VIII

    

    wherein
    n, m, p, A, X, W¹, W² and R¹ to R¹⁰ have the meanings given in claims 1 to 5, is cyclised and
    if necessary, a hydroxy group which may be present in a compound of the formula IV is protected by a suitable protecting group before carrying out reaction b) and the protecting group is removed again after the reaction is complete and/or
    if appropriate, a hydroxy group present in a compound of the general formula VI is converted into the corresponding ester group when carrying out reaction c) by the use of two equivalents of a compound of the general formula VII and the ester group is then saponified again, or
    a compound of the general formula I thus obtained is converted into its salt using an inorganic or organic acid.